DECISION OF COUNCIL OF THE EURASIAN ECONOMIC COMMISSION

of November 3, 2016 No. 85

About approval of Rules of carrying out researches of bioequivalence of medicines within the Eurasian Economic Union

According to Item 2 of Article 4 and article 6 of the Agreement on the single principles and rules of drug circulation within the Eurasian Economic Union of December 23, 2014, Item 86 of appendix No. 1 to the Regulations of work of the Eurasian economic commission approved by the Decision of the Supreme Eurasian economic council of December 23, 2014 No. 98, and the Decision of the Supreme Eurasian economic council of December 23, 2014 "About implementation of the Agreement on the single principles and rules of drug circulation within the Eurasian Economic Union" Council of the Eurasian economic commission solved No. 108:

1. Approve the enclosed Rules of carrying out researches of bioequivalence of medicines within the Eurasian Economic Union.

2. This Decision becomes effective after 10 calendar days from the effective date of the Protocol signed on December 2, 2015 on accession of the Republic of Armenia to the Agreement on the single principles and rules of drug circulation within the Eurasian Economic Union of December 23, 2014, but not earlier than after 10 calendar days from the date of official publication of this Decision.

Members of council of the Eurasian economic commission: From the Republic of Armenia

V. Gabriyelyan

From the Republic Belarus

V. Matyushevsky

From the Republic of Kazakhstan

A. Mamin

From the Kyrgyz Republic

O. Pankratov

From the Russian Federation

I. Shuvalov

Approved by the Decision of Council of the Eurasian economic commission of November 3, 2016 No. 85

Rules of carrying out researches of bioequivalence of medicines within the Eurasian Economic Union

I. General provisions

1. These rules establish requirements to development of design of researches of bioequivalence (the general plan of researches, the description of methods of carrying out researches depending on selection and forming of groups of subjects of researches, masking of data), to carrying out researches of bioequivalence and the analysis of their results, and also the bases for replacement of the researches in vivo with the researches in vitro.

The purpose of carrying out researches of bioequivalence - to prove equivalence of the reproduced (hybrid) medicine to reference medicine on quality to extrapolate results of the preclinical testing and clinical trials conducted concerning reference medicine to the reproduced (hybrid) medicine. Carrying out researches of bioequivalence is required in case of modification of the registration file of the registered medicine (in particular, in case of change of composition of excipients, the production technology, production sites, enlargement or disaggregation of industrial series, etc.), at preregistration stage in case of essential change of structure, the production technology of medicine (if the main preclinical and clinical trials are conducted with not changed medicine and it is necessary to extrapolate the obtained data on safety and efficiency to the changed medicine), in case of change of dosage form with immediate release on dosage form with the modified release, development of the combined medicines and in other cases.

2. Two medicines containing identical amount of active ingredient are considered bioequivalent if they are pharmaceutical equivalent or pharmaceutical alternative and their bioavailability (on the speed and degree) after use in identical molar dose keeps within predefined admissible limits. The specified limits are set for ensuring comparability of biopharmaceutical properties of dosage form in which in vivo drugs are produced (that is their comparabilities by efficiency and safety).

3. For determination of speed and extent of absorption in researches of bioequivalence the curve "concentration - time" is usually used. The following pharmacokinetic parameters and predefined borders of their acceptable deviations allow to judge bioequivalence of the compared medicines by assessment of their comparative bioavailability:

the area under curve "concentration - time" (AUC), reflecting exposure size;

the maximum concentration of substance (Cmax) in blood, plasma or serum (further also - plasma, bioliquid);

time of achievement of the maximum concentration in bioliquid (tmax).

Under this Cmax and tmax are parameters on which the speed of absorption of active ingredient from dosage form exerts impact.

4. These rules extend to medicines in the form of firm dosage forms for intake with immediate release of active ingredient, contain requirements to planning and carrying out researches of bioequivalence by studying of comparative bioavailability of kinds of these dosage forms with immediate release, and also other types of dosage forms according to general requirements according to appendix No. 1.

Development of design and carrying out researches, data analysis of comparative bioavailability for confirmation of bioequivalence of dosage forms of such medicines are carried out according to requirements of the Section III of these rules. If bioequivalence cannot be confirmed by means of bioavailability researches, phracodynamic or clinical trials, according to requirements according to appendices No. No. 2 and 3 are carried out. Development of design and carrying out researches, data analysis of comparative bioavailability for confirmation of bioequivalence of medicines in the dosage forms intended for rendering local action or for topical administration are carried out according to requirements according to appendices No. 11 - 13.

5. In these rules criteria according to which carrying out researches of bioavailability of in vivo is not required (for additional dosages - according to subsection 7 of the Section III of these rules, for separate types of dosage forms - according to appendix No. 1, for the procedure bioveyver based on biopharmaceutical classification system - according to appendix No. 4) are established.

6. In case of confirmation of bioequivalence of medicines which are issued in dosage forms with the modified release transdermalny dosage forms and inhalation dosage forms, and also dosage forms for topical administration and liposomal dosage forms researches should be conducted according to requirements of appendices No. 9 and 10, and also with the acts entering the right of the Eurasian Economic Union (further - the Union) in the field of drug circulation.

7. Scope of these rules is limited to comparison of chemical compounds. Procedure for comparison of biological medicines with reference medicines are established in rules of carrying out researches of the biological medicines within the Eurasian Economic Union approved by the Eurasian economic commission (further - the Commission). Confirmation of bioequivalence can be carried out concerning vegetable medicines, but the main requirements stated in these rules are not applicable to vegetable medicines for which active ingredients are not fully characterized.

8. These rules are used in case of filing of applications about registration of medicines within the Union.

9. The researched medicines used in bioequivalence research shall be made according to requirements of the rules of proper production practice of the Eurasian Economic Union approved by the Commission with representation of the corresponding documentary confirmation in the registration file.

The bioequivalence researches conducted outside the territory of the Union shall correspond to the these rules and other acts entering the right of the Union in the field of drug circulation.

10. On the questions which are not settled in these rules, applicants have the right to address to Expert committee on medicines (further - Expert committee) behind consultation.

II. Determinations

11. For the purposes of these rules concepts which mean the following are used:

"bioveyver" (biowaiver) - assessment procedure of bioequivalence of medicine without carrying out the research in vivo;

"biological availability", "bioavailability" (bioavailability) - the speed and degree with which active ingredient or active part of molecule of active ingredient are absorbed from medicine and become available in the place of the action. Bioavailability is determined as absolute or relative measure.

Absolute bioavailability of active ingredient (active part of molecule of active ingredient) in certain dosage form is determined by comparison with bioavailability of this active ingredient (active part of active ingredient) in case of its intravascular introduction, the last is equated to 100 percent (for example, solution for intake in comparison with solution for intravenous administration).

Relative bioavailability of active ingredient (active part of molecule of active ingredient) in certain dosage form is determined by comparison with bioavailability of other dosage form entered by the same or another (but not intravenous) way (for example, tablets in comparison with solution for intake).

Basis of carrying out researches of bioequivalence and bioavailability of the majority of medicines is determination of relative bioavailability.

Bioavailability of the medicines which are not assuming absorption in blood stream is allowed to be estimated by means of the parameters capable to reflect the speed and degree of availability of active ingredient or active part of molecule of active ingredient in the place of the action;

"bioequivalence" (bioequivalence) - lack of significant distinctions on the speed and degree with which active ingredient or active part of molecule of active ingredient of pharmaceutical equivalents or pharmaceutical alternatives become available in the place of the action in case of introduction in identical molar dose in similar conditions in research with proper design. With intended distinctions in speed (for example, some dosage forms with the modified release), certain pharmaceutical equivalents and pharmaceutical alternatives can be acknowledged bioequivalent if there are no significant distinctions in degree with which active ingredient or active part of molecule of active ingredient from each medicine become available in the place of the action. The rule is applicable only in case of distinction in the speed with which active ingredient or active part of molecule of active ingredient become available in the place of the action, are planned and reflected in general characteristic of medicine, are not significant for achievement of effective concentration of active ingredient or active part of molecule of active ingredient in organism in case of prolonged use and from the medical point of view are acknowledged insignificant for medicine.

Studying of bioequivalence can be performed as in the conditions of in vivo (pharmacokinetic, phracodynamic, clinical trials), and in vitro (for example, researches of the test of comparative kinetics of dissolution);

"biopharmaceutical classification system" (biopharmaceutics classification system, BCS, BSK) - the scientific approach allowing to divide active ingredients of medicines based on degree of their solubility in water and intestinal permeability. Together with the test of kinetics of dissolution for BSK medicine considers 3 major factors influencing the speed and extent of absorption of active ingredients from dosage forms with immediate release for intake: dissolution, solubility and intestinal permeability;

"the reproduced medicine", "generic" - the medicine having the same high-quality and quantitative composition of active ingredients (active pharmaceutical substances) and the same dosage form, as reference medicine and which bioequivalence to reference medicine is confirmed by the corresponding researches of bioavailability.

Different salts, ethers, isomers, mixes of isomers, complexes or derivatives of active ingredient are recognized the same active ingredient if their safety and (or) efficiency significantly do not differ. Different dosage forms for intake with immediate release are recognized within the bioavailability researches the same dosage form (from the biopharmaceutical point of view);

"hybrid medicine" - the medicine which is not falling under determination of the reproduced medicine given in these rules or, in case of impossibility of confirmation of its bioequivalence by means of bioavailability researches and also if active ingredient (active ingredients), indications to use, the dosage, dosage form or way of introduction of such medicine differ from those reference medicine that requires representation of results of preclinical and (or) clinical trials;

"medicine dose" (dose) - amount of active ingredient of medicine on 1 use (single or repeated use);

"medicine dosage" (strength) - quantitatively expressed content of active ingredients in unit of dosing, amount or weight according to dosage form;

"testing "dissolution" for quality control" (quality control dissolution test) - the testing provided by the Pharmacopoeia of the Union which is carried out for the purpose of routine quality control of series of medicine in the form of testing for dissolution with one control temporary period for sampling for medicines with immediate release and with 3 and more control temporary periods for medicines with the modified release;

"the combined medicine" (fixed-dose combination finished pharmaceutical product, FDC-FPP, KLP) - the ready medicine containing 2 and more active ingredients (active pharmaceutical substances);

"dosage form" (dosage form) - the medicine condition corresponding to methods of its introduction and use and providing achievement of necessary effect;

"fillers" - kind of the excipients used for giving to firm dosage forms of given size;

"original medicine" (innovator pharmaceutical product) - medicine with new active ingredient which was registered and placed by the first in the world pharmaceutical market based on the registration file containing results of the complete preclinical (not clinical) and clinical trials confirming its quality, safety and efficiency, equivalent on content to the requirements established by part I of appendix No. 1 to Rules of registration and examination of medicines for medical application;

"reference medicine", "comparison medicine", "comparator", "control" (comparator product) - medicine which is used as standard in researches of comparative bioavailability for regulation of the researched parameters;

"the reduced file" - the registration file of medicine which amount of pharmaceutical development does not provide performing complete toxicological and clinical trials and inclusion of their results in modules 4 and 5 of the registration file;

"the test of comparative kinetics of dissolution in vitro" (in vitro equivalence dissolution test, TSKR) - the testing including comparison of profiles of dissolution of the researched medicine and reference medicine, as a rule, in 3 circles - buffered solutions with pH 1, 2; 4,5 and 6,8;

"pharmaceutical equivalence", "pharmaceutical equivalents" (pharmaceutical equivalence) - medicines in identical dosage forms which contain identical amount of identical active ingredient (active pharmaceutical substance) that is identical salt or ether of the same active part of molecule of active ingredient or in dosage forms with the modified release requiring creation of the reservoir or excess or in such forms as previously filled syringes (in which can vary residual amount), which bring identical amount of active ingredient during the identical period of dosing. Pharmaceutical equivalents optionally contain identical inactive ingredients. They satisfy to identical pharmacopoeian or other applicable standards on authenticity, dosage, quality and purity, including activity and in applicable cases on uniformity of content, time of raspadeniye and (or) speed of dissolution;

"pharmaceutical alternative medicines (pharmaceutical alternatives)" - the medicines containing identical active part of molecule of active ingredient or its predecessor (precursor) optionally in identical quantity, or dosage form or in the form of the same salt or the same ether. Each such medicine in individual procedure satisfies to the identical or own conforming pharmacopoeian or other applicable standards on authenticity, dosage, quality and purity (including activity and in applicable cases uniformity of content, time of raspadeniye and (or) speed of dissolution);

"the fixed combination of doses" (fixed-dose combination, FDC, FKD) - combination of 2 and more active ingredients with the established ratio of dosages. FKD is used for designation of specific combination of active ingredients regardless of structure or the trade name of medicine. The combination of active ingredients can be used as set of the monocomponent medicines used at the same time and in the form of ready multicomponent medicine.

For the purpose of these rules significant are understood as all researches of medicine which exert impact on information on its safety, quality, the efficiency and area of possible clinical use declared in general characteristic of medicine.

III. Requirements to design, carrying out and assessment of researches of bioequivalence

12. The amount and design of researches of bioequivalence need to be proved by physical and chemical and pharmacokinetic properties of active ingredient and proportionality of composition of medicine. In particular, it is necessary to consider linearity of pharmacokinetics, need of carrying out research depending on meal, the analysis of enantiomer, and also feasibility of carrying out researches of additional dosages (according to requirements of subsections 4 - 7 these Sections).

13. In the module of 2.7.1 registration files in format of the general technical document it is necessary to provide the list of all significant researches (irrespective of their results) conducted with medicine, including bioequivalence researches for the purpose of comparison of the medicine declared to registration (that is having the same structure and production process) with reference medicine (according to requirements of subsection 2 of this Section).

Concerning all the conducted researches as a part of the module of the 5th registration file it is necessary to submit complete reports, except for pilot researches for which if they were carried out, it is enough to give short synopses which are drawn up according to appendix No. 2 to the rules of proper clinical practice of the Union approved by the Commission. The complete report on pilot researches, in this case, needs to be submitted upon the demand of authorized bodies of state members of the Union (further - state members). It is also necessary to include in the module 2.7 synopses of reports on the researches of bioequivalence and comparative bioavailability conducted at medicine development stage.

1. Design of research

14. The design of research needs to be constituted so that influence of medicine on its pharmacokinetic parameters could be distinguished from influence of other factors.

15. The standard design assumes the following.

When comparing 2 medicines it is recommended to conduct randomized, two-period, cross research in 2 sequences with acceptance of single dose. The periods shall be divided by the washout period sufficient for decrease in concentration of active ingredient is lower than threshold of bioanalytical determination at all subjects at the beginning of the second period of research. Usually for this purpose there is enough 5 elimination half-lives.

16. The alternative design assumes the following.

In certain cases, that the design of research and statistic analysis are evidence-based it is possible to consider the alternative conventional designs: parallel - for substances with long t1/2; repeated (replikativny, replicate design) - for substances with highly variable pharmacokinetic parameters (according to requirements of subsection 11 of this Section).

17. If owing to intolerance acceptance of single dose by healthy volunteers is inadmissible, and the research of single dose at patients cannot be conducted, carrying out research at patients with multiple dose of medicine is allowed.

In rare instances when insufficient sensitivity of analytical method interferes with exact determination of concentration in biological liquid after acceptance of single dose, and equilibrium concentration is rather high for receipt of exact values, as an alternative to research with acceptance of single dose carrying out research with multiple dose of medicine is admissible. However, in view of that researches with multiple dose are less sensitive for determination of distinctions in Cmax, their carrying out is admissible only if the applicant is able to prove definitively that sensitivity of analytical method cannot be improved and that after acceptance of single dose of medicine precisely it is impossible to measure concentration of initial connection, considering that in researches of bioequivalence it is admissible, having provided the corresponding reasons, to use the doses exceeding therapeutic (according to requirements of subsection 7 of this Section). Carrying out research with multiple dose of medicine instead of analytical method, single owing to insufficient sensitivity, is admissible only in exceptional cases.

In researches of equilibrium concentration the washout period after acceptance of the previous medicine can block increase of concentration in the second period (provided that duration of such increase rather long and constitutes at least 5 final t1/2).

2. Reference medicine and the researched medicine

Reference medicine

18. In case of the choice of reference medicine proceed from the following sequence:

a) original medicine which safety, efficiency and quality were established in case of registration in the Union, and also registered according to the legislation of state members ("the original drug registered in the Union");

b) the original medicine registered in the countries of the region of the International council on harmonization of technical requirements to medicines for medical application (ICH), or in case of reasons for its absence in the address in the pharmaceutical market of the countries of the region of ICH or impossibility of its acquisition reproduced (or hybrid) the medicine registered at least in one of state members and which confirmed the bioequivalence to original medicine (in case of approval of the choice of the reproduced drug by Expert committee), in case of impossibility of accomplishment of the subitem "an" of this Item;

c) the medicines approved by Expert committee (the list of decisions is posted on the official site of the Union), in case of impossibility of accomplishment of subitems "an" and "b" of this Item;

d) the medicine having experience of use in the territory of at least one of state members at least 20 years (in case of approval by Expert committee), in case of impossibility of accomplishment of subitems "an" - "in" this Item;

e) the combined medicine considered and approved by Expert committee in case of impossibility of accomplishment of subitems "a" - this Item.

Expert committee the choice as the reference combined medicine containing the known active ingredients and registered at least in one of state members in case of the limited program of its studying which is not allowing to recognize originality, can be made taking into account assessment of duration of medical application of drug and justification of creation of the fixed combination, in case of impossibility of accomplishment of subitems "a" - "" of this Item.

In case of impossibility to recognize medicine reference because of irrationality of combination, unproven efficiency and safety for development of new medicine carrying out the program of preclinical and clinical trials is offered, to the corresponding development of new combinations, according to acts of bodies of the Union in the field of drug circulation.

19. In case of research of the reproduced (hybrid) medicine or modification and amendments in the registration file of medicine regarding active ingredients, dosages, dosage form and way of introduction compare the researched medicine to the corresponding dosage form and dosage of reference medicine (if provisions of paragraph two of this Item are not applicable).

If original medicine is presented at the market in several dosage forms, as reference medicine it is recommended to use that from them in the form of which it was for the first time registered and which was used in clinical trials for confirmation of its efficiency and safety.

20. The applicant shall prove the choice of reference medicine for bioequivalence research taking into account results of quantitative determination of content of active ingredient and data on its dissolution. In the series which is subject to use as the researched medicine, the quantitative content (established by means of the analytical technique offered for standard quality tests of the researched drug, included in the specification (the regulating document on quality control)) shall not differ more than for 5 percent from series of reference medicine (in the absence of due reasons). The applicant by means of TSKR and quantitative determination of active ingredient shall prove the choice of the series of reference medicine planned to studying in bioequivalence research. In case of the choice of series of reference medicine for research of bioequivalence it is recommended to study several series of reference medicine.

The researched medicine

21. The researched medicine which is subject to use in bioequivalence research shall not differ from medicine (on structure, the production technology, production equipment) which will come to the pharmaceutical market of the Union that shall be considered and proved by the applicant.

22. For firm dosage forms for intake of system action the following rules are effective (complete requirements to validation of production process contain in the rules of proper production practice of the Union and other acts entering the right of the Union in the field of drug circulation):

a) for lack of due reasons the researched medicine shall be selected from the series constituting, at least, 1/10 industrial series, or 100 000 units of dosage forms depending on what of amounts is more;

b) production of the used series of medicine shall provide high degree of confidence that medicine and process of its production will be reproduced in industrial scale.

The amount of the series intended for confirmation of bioequivalence of less than 100 000 units is possible provided that it is the offered amount of serial production, and the subsequent scaling of batches is not supposed;

c) the description of properties and creation of the specification on such critical indicators of quality of medicine as dissolution, it is necessary to perform, using the researched series, i.e. the series studied in clinical trials concerning which bioequivalence is confirmed;

d) the medicine samples from additional trial and (or) industrial series provided on registration need to be compared to samples from the series used in bioequivalence research; they shall have comparable profiles of dissolution in vitro in suitable conditions of TSKR (according to appendix No. 5).

23. Concerning each of the first three industrial series before release they on the market of the Union need to be carried out by TSKR with the series used in bioequivalence research. In case of the expiration of its period of validity as reference the previous industrial series which profile of dissolution was comparable to profile of dissolution of the series used in bioequivalence research can be used.

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