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DECISION OF COUNCIL OF THE EURASIAN ECONOMIC COMMISSION

of November 3, 2016 No. 78

About Rules of registration and examination of medicines for medical application

(as amended on 23-12-2020)

According to article 7 of the Agreement on the single principles and rules of drug circulation within the Eurasian Economic Union of December 23, 2014, Item 84 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 registration and examination of medicines for medical application (further - Rules).

2. Determine that:

a) registration, registration confirmation (re-registration), modification of the registration file and other procedures connected with registration of medicines for medical application, stipulated by the legislation state members of the Eurasian Economic Union (further respectively - state members, the Union) and not completed by authorized bodies of state members till January 1, 2016, are performed according to the legislation of state members;

b) till July 1, 2021 (in the Russian Federation - till December 31, 2020) at the choice of the applicant registration of medicine can be performed either according to Rules, or according to the legislation of state member. At the same time the medicines registered according to the legislation of state member are allowed to the address only in the territory of state member which authorized body issued the registration certificate;

c) action of registration certificates of the medicines issued by authorized bodies of state members till July 1, 2021 can be prolonged according to the legislation of state members, but no more than till December 31, 2025. At the same time modification of the registration files of such medicines created according to the legislation of state members is performed according to the legislation of state members no later than December 31, 2025;

d) the medicines registered according to the legislation of state members shall be brought into accord with requirements of the international treaties and acts constituting the right of the Union till December 31, 2025;

e) the registration certificates of medicines issued according to the legislation of state members are valid before the termination of term of their action, but no later than December 31, 2025.

3. To state members till December 31, 2016:

a) approve the amount of charges (duties) or other obligatory payments provided by Rules taking into account complexity of the procedures and amount of works which are carried out in the reference state and the states of recognition including in case of:

medicine registration;

registration confirmation (re-registration) of medicine;

reduction of the registration file of medicine in compliance with requirements of the international treaties and acts constituting the right of the Union;

b) determine bodies (organizations) authorized on registration implementation, registration confirmation (re-registrations), modification of the registration file and other procedures provided by Rules connected with registration of medicines for medical application and to inform on it the Eurasian economic commission.

4. 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 of 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 Euroasian economic commission of November 3, 2016 No. 78

Rules of registration and examination of medicines for medical application

I. General provisions

1. These rules determine procedure of registration, registration confirmation (re-registration), modification of the registration file and examinations of medicines for medical application for the purpose of forming of the total market of medicines within the Eurasian Economic Union (further - the Union), and also other medicines connected with registration for medical application of the procedures (further - the procedures connected with registration) including:

a) reduction of the registration file of the medicine registered in state members of the Union (further - state members) before entry into force of the Agreement on the single principles and rules of drug circulation within the Eurasian Economic Union of December 23, 2014 (further - the Agreement) and till December 31, 2020, in compliance with these rules (further - reduction in compliance with requirements of the Union);

b) suspension and cancellation of registration of medicines or restriction of use of medicine;

c) issue of duplicates of the registration certificate of medicine.

2. Requirements of these rules extend to developers and producers of medicines, holders of registration certificates of medicines, their authorized representatives, authorized bodies (the expert organizations) of state members in the field of drug circulation.

3. Requirements of these rules are not applied in the relation:

a) medicines which are intended for use in the conditions of military operations of emergency situations, for prevention and treatment of the diseases and defeats received as a result of impact of chemical, biological, radiation factors are developed on the instructions of representatives in the field of safety and defense of public authorities of state members and which address is regulated by the legislation of state members;

b) veterinary medicines which address is regulated by other acts entering the right of the Union.

4. The medicines intended for the address in the total market of medicines within the Union or in the territory of one of state members are subject to registration according to these rules.

5. Are not subject to registration within the Union:

a) the medicines made in drugstores;

b) pharmaceutical substances;

c) the medicines intended for performing preclinical and clinical trials;

d) the medicines imported by physical persons for personal use;

e) the radio pharmaceutical medicines made directly in the medical organizations according to the procedure, established by authorized bodies;

e) the medicines which are not intended for realization on customs area of the Union;

g) the samples of medicines intended for registration and standard samples;

h) medicines, held for use as exhibition samples.

6. In case of medicine recognition orphan in the territories of all or several state members according to the legislation of state members registration of such medicine is performed according to Sections V and VII or Sections VI and VII of these rules, and also according to requirements of the Section 16 of part III of appendix No. 1 to these rules.

In case of medicine non-recognition orphan in the territory of any state member according to the legislation of this state registration of such medicine is performed in this state according to requirements of subsection I of the Section V of these rules and appendices No. 1 to these rules.

7. Registration under one trade name of the medicines having different high-quality composition of active ingredients is forbidden.

8. Registration of one medicine with different trade names in different state members in the following cases is allowed:

a) use of the offered trade name can contradict rules of law and morals or otherwise does not consider national cultural and (or) tongue peculiarities;

b) the intellectual rights to the trade name in the form of the trademark belong to person differing from the face, the medicine which submitted the registration application (further - the applicant), or the holder of the registration certificate, and the applicant or the holder of the registration certificate cannot grant the corresponding license agreement about provision right to use of the trademark;

c) medicine was registered under different trade names according to the legislation of state members till December 31, 2020

9. Medicine registration, registration confirmation (re-registration), modification of the registration file, and also the procedures connected with registration are performed by authorized bodies.

10. Examination of medicine is performed by the expert organization determined according to the legislation of state member.

11. Authorized bodies and the expert organizations provide confidentiality of information containing in the registration file of medicine in the course of implementation of registration and examination of medicines, including information containing in the closed part of the master file on active pharmaceutical substance.

The Eurasian economic commission (further - the Commission) and Expert committee on medicines (further - Expert committee) provide confidentiality of the information containing in the registration file of medicine, received in the course of implementation of the activities.

12. The applicant according to the legislation of state member incurs expenses on registration, registration confirmation (re-registration), modification of the registration file and the examination of medicines, procedures connected with registration, and also on conducting inspections for the purpose of determination of compliance to requirements proper pharmaceutical the practician, the specified procedures initiated in connection with implementation.

13. To the applicant the expenses specified in Item 12 of these rules do not return.

14. The authorized body (the expert organization) of the reference state in case of receipt of the registration application, registration confirmation (re-registration), modification of the registration file and the procedures connected with registration assigns it the unique number created with use of the integrated information system of the Union (further - the integrated system), and tells it to the applicant.

15. The authorized body (the expert organization) of state member provides information connected with implementation of registration, registration confirmation (re-registration), modification of the registration file and also the procedures connected with registration, to authorized bodies (the expert organizations) of other state members and also in the Commission with use of the integrated system on number of the statement according to procedure for forming and maintaining the Unified register of the registered medicines (further - the unified register).

The authorized body (the expert organization) of the reference state no later than 5 working days from the date of submission of the registration file in electronic form by the applicant provides access to data of the registration file at the request of authorized bodies (the expert organizations) of the states of recognition by means of use of means of the integrated system.

16. By results of medicine registration the authorized body of each state member which registered medicine issues the registration certificate of medicine confirming the fact of its registration.

17. The registration certificate of medicine is issued in single form and according to rules of filling of the registration certificate of medicine for medical application according to appendix No. 17 to these rules by the authorized body which registered medicine.

During the losing or damage of the registration certificate of medicine according to the statement of the holder of the registration certificate for issue of the duplicate of the registration certificate of medicine the authorized body which issued this registration certificate issues its duplicate which is drawn up according to rules of filling according to appendix No. 17 to these rules.

18. Effective period of the registration certificate on for the first time constitutes the registered medicine in the reference state 5 years. After the specified term the termless registration certificate of medicine on condition of confirmation of its registration (re-registration) is issued. In the cases specified in the Section VII of these rules, and also in the cases connected with pharmakonadzor questions, the authorized body can repeatedly issue the registration certificate with effective period of 5 years following the results of registration confirmation (re-registration).

The registration certificate of the medicine registered according to the legislation of state members till December 31, 2020, and which is traded 5 years and more on the market at least 3 state members is issued for unrestricted term within the procedure of reduction in compliance with requirements of the Union according to the Section XIII of these rules.

II. Determinations

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

"allergen" - any medicine intended to reveal or cause the specific acquired change of immunological reaction to the substance causing allergy;

"safety of medicine (ratio "advantage - risk")" - assessment of positive therapeutic effects of medicine in relation to the risks connected with its use (the concept of risk includes any risk connected with quality, safety or efficiency of medicine in relation to health of the patient or the population);

"biosimilar medicine (bioanalogue, biosimilar medicine, biosimilyar)" - biological medicine which contains the version of active ingredient of the registered biological original (reference) drug and for which similarity (similarity) on the basis of comparative researches with reference drug on indicators of quality, biological activity, efficiency and safety is shown;

"biological availability (bioavailability)" - the speed and degree with which active ingredient or its active part of molecule from the dosed dosage form are soaked up and become available in the scene of action;

"biological equivalence (bioequivalence)" - lack of significant distinctions in 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;

"biological medicine" - medicine which active ingredient is made or emitted from biological source and the description of properties and which quality control requires combination of biological and physical and chemical methods of the analysis to assessment of production process and methods of its control;

"the reproduced medicine (generic)" - medicine which has the same quantitative and high-quality composition of active ingredients and the same dosage form, as original drug and which bioequivalence to original 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 efficiency significantly do not differ. Different dosage forms for intake with immediate release are recognized within the bioavailability researches the same dosage form;

"the radionuclide generator" - any system containing the fixed primary radionuclide of which the secondary radionuclides which are extracted by eluating or in a different way and used in radio pharmaceutical medicine are formed;

"hybrid medicine" - the medicine which is not falling under determination of the reproduced medicine in case of impossibility of confirmation of its bioequivalence by means of bioavailability researches and also if in this drug there were changes of active ingredient (substances), indications to use, dosages, dosage form or way of introduction in comparison with original drug;

"homeopathic medicine" - the medicine made on homeopathic technology with use of homeopathic raw materials according to requirements of the Pharmacopoeia of the Union or in case of their absence according to requirements of homeopathic pharmacopeias;

"the state of recognition" - state member in which medicine is registered (is registered) with conducting the examination including assessment of the expert valuation report of safety, efficiency and quality of the medicine prepared by the reference state;

"the holder of the registration certificate" - the legal entity addressed to whom the registration certificate on medicine is issued and which bears responsibility for safety, efficiency and quality of medicine;

"the unified register of the registered medicines of the Union" - the general information resource created within the integrated system and containing data on the medicines registered or which underwent other procedures connected with registration according to these rules;

"applicant" - the legal entity, competent to submit the registration application, registration confirmation (re-registration), modification of the registration file of medicines, other procedures connected with the registration, and bearing responsibility for accuracy of the information containing in the documents and data of the registration file submitted by it;

"immunological medicine (immunobiological medicine)" - the medicine intended for forming of active or passive immunity, either diagnosis of availability of immunity, or diagnosis (development) of the specific acquired change of the immunological answer to allergenic substances;

"the instruction on medical application (leaf insert)" - the document approved by authorized body of state member according to acts of bodies of the Union, containing information for the consumer and accompanying medicine in packaging;

"quality of medicine" - the set of properties and characteristics of pharmaceutical substance and medicine providing their compliance to purpose according to requirements of acts of bodies of the Union;

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

"medicinal vegetable raw materials" - the fresh or dried-up plants, seaweed, mushrooms or lichens or their parts, integral or crushed, used for production of medicines;

"medicine with well studied medical application" - medicine which active ingredient is well studied during medical application at the same time its efficiency and acceptable degree of safety confirmed with detailed bibliographic references to the published data on post-registration and (or) epidemiological researches are acknowledged and there passed at least 10 years from the date of the first systematic and documentary use of active ingredient (active ingredients) of this medicine at least in 3 state members;

"medicinal vegetable drug" - the medicine containing in quality of active components exclusively medicinal vegetable raw materials and (or) drugs on its basis;

"international non-proprietary name" - the name of active ingredient recommended by the World Health Organization;

"the regulating document on quality" - the document which establishes requirements to medicine quality control (containing the specification and the description of analytical techniques and testing or the reference to them, and also the corresponding eligibility criterions for the specified quality indicators, etc.) based on the carried-out medicine expertize affirms authorized body in case of registration for the territories of the Union and is intended for quality control of medicine during the post-registration period in the territory of the Union;

"general characteristic of medicine" - the document approved by authorized body of state member, according to acts of bodies of the Union, containing information for health workers on safe and effective use of medicine;

"the commonly accepted (grouping) name" - the name of the medicine which does not have the international non-proprietary name, or combinations of medicines used for the purpose of their consolidation in group under the single name proceeding from identical high-quality composition of active ingredients;

"original medicine" - medicine with new active ingredient which was registered and placed by the first in the world pharmaceutical market based on the file containing results of the complete preclinical (not clinical) and clinical trials confirming its quality, safety and efficiency;

"orphan (rare) medicine" - the medicine intended for diagnosis, etiopatogenetichesky or pathogenetic treatment (the treatment directed to the disease development mechanism) of rare (orphan) diseases which frequency does not exceed officially certain level in state member;

"the representative of the holder of the registration certificate" - the legal entity registered according to the legislation of state member, or the separate division of the legal entity located in the territory of state member and authorized by the holder of the registration certificate on accomplishment of the actions connected with drug circulation in the territory of state member;

"producer of medicines" - the organization which is performing activities for production of medicines and having permission (license) for such type of activity issued by authorized body of the manufacturing country;

"radio pharmaceutical medicine" - the medicine containing in condition, ready for use, one or several radionuclides (radioactive isotopes) as active ingredient or as a part of active ingredient;

"vegetable pharmaceutical substance" - the substance received after processing of vegetable raw materials by means of such methods as extraction, distillation, extraction, fractionation, cleaning, concoction and fermentation. Melkoizmelchenny or powdery vegetable raw materials, tinctures, extracts, essential oils, the wrung-out juice and the processed extracts belong to such substances;

"the registration file" - the set of the documents (including the statement) which are drawn up according to these rules, represented for holding the procedures connected with registration, registration confirmation (re-registration) of medicine;

"the registration certificate of medicine" - the document of single form issued by authorized body, confirming the fact of registration of medicine and which is permission for its medical application in the territory of state member;

"registration number" - the specification symbol appropriated to medicine upon registration for the state member territories;

"medicine registration" - the process of receipt of permission for medical application of medicine in the territories of one or several state members performed according to these rules;

"the reference state" - the state member performing preparation of the expert valuation report of safety, efficiency and quality of medicine based on examination of medicine according to these rules;

"reference medicine" - medicine which is used as drug of comparison and is standard by which are determined properties of medicine (are normalized);

"the risks connected using medicine" - any risks connected with quality, safety or efficiency of medicine concerning health of patients or the population or the risks leading to undesirable impact on the environment;

"specification" - the list of indicators of quality, references to the analytical techniques and testing and regulations representing numerical (quantitative) limits, the ranges and other criteria for the specified quality indicators;

"standard sample" - the identified homogenous matter or mix of substances, held for use in chemical, physical and biological researches in which its properties are compared to properties of the researched medicine, and having purity degree, sufficient for the corresponding use;

"the trade name of medicine" - the name under which medicine is registered;

"pharmaceutical substance (active pharmaceutical substance)" - the medicine intended for production and production of medicines;

"the expert valuation report of safety, efficiency and quality (expert valuation report)" - the document containing results of examination of safety, efficiency and quality of medicine and the conclusion about opportunity (or impossibility) its registration, registration confirmation (re-registration), modification of the registration file, reduction of compliance with requirements of the Union, prepared by the expert organization of the reference state;

"efficiency of medicine" - set of the characteristics providing achievement of preventive, diagnostic or medical effect or recovery, correction or modification of physiological function.

III. General principles of registration of medicines

20. Registration of medicines can be performed upon the demand of the applicant consistently in several state members according to the procedure of mutual recognition or at the same time in several state members according to the decentralized procedure of registration.

21. The procedure of mutual recognition is performed:

a) the reference state according to these rules for the purpose of the address of medicine in the market only this state (the national procedure of registration);

b) in the states of recognition - at the request of the applicant after registration of medicine in the reference state according to the procedure of mutual recognition.

22. The decentralized procedure of registration is performed at the same time by several state members to which the application for medicine registration, with the choice of the reference state is submitted.

23. The applicant independently performs the choice of the reference state and in need of the state of recognition in case of filing of application on medicine registration.

24. Only one state can act as the reference state.

25. Requirements to documents and data of the registration file in format of the general technical document submitted on medicine registration are established by appendices No. 1 - 5 to these rules.

26. Before filing of application on medicine registration authorized bodies or the expert organizations of state members have the right to hold at the request of the applicant scientific and preregistration consultations according to the legislation of state members, on the questions connected with carrying out analytical testing, preclinical and clinical trials (testing), to aspects of the procedure of registration including on the questions concerning qualification, kind of the registration application of medicine for the purpose of scoping of documents and data of the registration file concerning completeness of the registration file, determination of affiliates in the states of recognition, format of filing of application and the registration file, need of provision of samples of medicine, standard samples, materials, specific reactants, consumable materials, necessary for conducting laboratory examination of quality in the expert organization or for its appointment, and for other questions.

27. The authorized body or the expert organization of the reference state in case of identification during procedures of registration, registration confirmation (re-registration), modification of the registration file or procedures connected with registration, the facts calling into question reliability of the data provided by the applicant in the registration file concerning the conducted preclinical (not clinical) trials (testing) of medicines and clinical trials (testing) of medicines or production of medicine including production of pharmaceutical substance or the organization of system of pharmakonadzor initiates carrying out by pharmaceutical inspectorate of this state of inspection on observance of proper relevant requirements pharmaceutical the practician. Such inspections can be also initiated in the cases specified in Items 31,33,35,37 - 39 these rules. Responsibility for timely initiation of the relevant unplanned inspectorates in case of their need is born by authorized body of the reference state.

28. Production of medicines shall correspond to Rules of proper production practice of the Eurasian Economic Union.

29. In case of filing of application on registration, registration confirmation (re-registration), reduction with requirements of the Union of medicine the applicant shall submit to compliance as a part of the registration file the existing document confirming compliance to requirements of proper production practice of the Union, the production site (production sites) performing production of ready dosage form and the issuing quality control of the medicine declared to registration, registration confirmation (re-registration), reduction in compliance with requirements of the Union.

Till December 31, 2020 concerning the production site (production sites) of medicine the applicant instead of the document confirming compliance to requirements of proper production practice of the Union having the right to submit the document confirming compliance to requirements of proper production practice issued to producer of medicine by authorized body of state members, the production site (production sites) of medicine performing production of ready dosage form and the issuing quality control.

30. In case of impossibility of submission of the existing document confirming compliance of the production site (production sites) of medicine to requirements of proper production practice of the Union the applicant in case of submission till December 31, 2020 of the registration application of medicine or on reduction with requirements of the Union instead of this document submits the following documents and data to compliance:

a) the existing documents confirming compliance of the production site (production sites) performing production of ready dosage form and the issuing medicine quality control, to requirements of proper production practice, the countries issued to producer of medicine by authorized body - producer of medicine;

b) the copy of the report on results of the last inspection of the production site (production sites at production phases) which is carried out by authorized body of the manufacturing country and (or) other authorized body within the last 3 years;

c) data on results of all inspections of this production site (production sites) on compliance to requirements of proper production practice which are carried out within the last 3 years;

d) data on claims concerning quality of the medicines made on this production site (production sites) for the last 3 years;

e) consent to conducting pharmaceutical inspection to compliance to requirements of proper production practice of the Union;

e) copy of the main file (master file) of the production site (production sites).

31. The reference state based on the documents submitted by the applicant specified in Item 30 of these rules taking into account assessment of possible risks makes the decision on need of conducting unplanned pharmaceutical inspection on compliance to requirements of proper production practice of the Union of holding registration procedures on medicine or in time on inclusion of inspection of the production site (production sites) on which production of the medicine declared on registration or for reduction in compliance with requirements of the Union including in need of pharmaceutical substance, in the plan of conducting inspections in the first 3 years after completion of registration procedures is performed.

32. In case of documentary reasons for impossibility of conducting unplanned inspection by authorized body of the reference state of the production site (production sites) for medicine by the reference state in terms of holding registration procedures concerning medicine the applicant has the right in coordination with the reference state to file in one of state members petition for conducting inspection of this production site (production sites) on compliance to requirements of proper production practice of the Union.

In case of written refusal of the states of recognition by authorized bodies in conducting unplanned inspection of the production site (production sites) of medicine, the authorized body of the reference state shall organize and carry out unplanned inspection to terms of holding registration procedures concerning medicine.

33. The decision on need of conducting unplanned pharmaceutical inspection on compliance to requirements of proper production practice of the Union is passed by authorized body of the reference state in the course of implementation:

a) procedures of registration - for the medicines made on the platforms performing production of ready dosage form and the issuing quality control, to earlier not being exposed inspection of at least one state member by authorized body (organization);

b) procedures of reduction in compliance with requirements of the Union - for the medicines which are earlier registered in state members in case of specifying (introduction, change) the production site (production sites) which was earlier not exposed to inspection of at least one state member by authorized body (organization).

34. Preclinical trials of safety of medicines are conducted according to requirements of the rules of proper laboratory practice of the Union approved by the Commission.

Clinical trials of medicines are conducted according to requirements of the rules of proper clinical practice of the Union approved by the Commission.

35. The preclinical trials of safety of medicines conducted in the states which are not members of the Union are considered in the course of examination of medicines provided that they are planned, carried out and described in the report on preclinical trial according to the requirements of proper laboratory practice equivalent to requirements of the Union (or not below).

The clinical trials of medicines conducted in the states which are not members of the Union are considered in the course of examination of medicines provided that they are planned, carried out and described in the report on clinical trial according to the requirements of proper clinical practice equivalent to requirements of the Union (or not below), and also the principles of the Helsinki declaration of the World Medical Association "Ethical principles of medical researches with participation of the person as research object".

In the course of medicine examination the authorized body of the reference state has the right to appoint unplanned inspection regarding observance of rules of proper laboratory practice of the Union in case:

identifications during conducting examination of medicine of the facts calling into question reliability of the results received during preclinical trials;

identifications doubtful (improbable or contradictory from the medicobiological point of view) results of researches;

availability of other circumstances provided by the rules of conducting pharmaceutical inspections approved by the Commission.

36. In case of medicine registration the reports on the conducted clinical trials included in its 5 registration files in structure of the module are considered in the course of examination in case of observance of one of the following conditions:

clinical trials are conducted according to the legislation of state members and in their territory till January 1, 2016 (by date of the last visit of the last patient (volunteer)) or continued to be carried out as of January 1, 2016 (in case of complete set of patients (volunteers) to research);

clinical trials are conducted in parts or in full in the territories of the countries of the region of the International conference on harmonization of technical requirements to registration of medicines for medical application (ICH) till January 1, 2016 (by date of the last visit of the last patient) based on which medicine is registered in the territories of the countries of the region of the International conference on harmonization of technical requirements to registration of medicines for medical application (ICH);

the clinical trials initiated after January 1, 2016 are carried out according to the international treaties and acts constituting the right of the Union, at the same time at least one of clinical trials is carried out fully or partially (concerning the data obtained from subjects of research) in the territory of the Union.

If the requirements specified in the second - the fourth paragraphs of this Item, are not carried out, before filing of application on medicine registration the applicant conducts clinical trials (at least one research on discretion of the applicant and in coordination with authorized body) fully or partially in the territory of the Union or when conducting examination of the registration file according to the decision of authorized body unplanned inspection of one of clinical centers in which clinical trial was conducted is appointed.

Provisions of this Item are not applied to orphan medicines.

37. The authorized body of the reference state based on the documents and data submitted by the applicant taking into account assessment of possible risks makes the decision on need (or lack of need) conducting unplanned inspection of clinical trials of medicine, including bioequivalence researches, carrying out registration of medicine for compliance to requirements of proper clinical practice of the Union or on inclusion of inspection of clinical trial in the plan of conducting inspections in the first 3 years after medicine registration in time. In this case planned inspection is carried out at least in one research center according to the rules of conducting pharmaceutical inspections approved by the Commission.

38. The decision on need of conducting unplanned inspection of clinical trial on compliance to requirements of proper clinical practice of the Union (or on compliance to requirements of proper laboratory practice of the Union - concerning applicable Items) is taken out by authorized body based on complex assessment of the following factors:

lack of information on approval of clinical trial by independent ethical committee;

identification of the facts of violation in receipt of the informed consent or information provided to subjects of research;

availability of the questions connected with administrative structure of clinical trial (absence or ambiguity of information);

availability of the essential amendments which are not reflected in the protocol during the research according to the rules of proper clinical practice approved by the Commission;

absence or insufficiency in the protocol and the report on clinical trial of the data describing measure definition of efficiency and (or) safety (concerning selection, identification, processing of clinical samples, conditions of quantitative determination);

availability of data on exception of these subjects of research of statistic analysis without reasons for the reasons;

identification of the facts calling into question reliability of the data provided in the registration file concerning clinical trial of medicine (unreasonable or not clear distinctions of final points of efficiency and safety in the protocol and the report of clinical trial; inconsistency, inaccuracy or incompleteness of data recording, change of the protocol are not considered in other documents of clinical trial, the large amount of the passed values capable to affect statistical capacity of research);

improbability or discrepancy of clinical data (contradictory results in comparison with the known results of other researches, the low frequency of messages on cases of serious undesirable reactions and (or) improbable data for benefit of the researched drug in comparison with results of other researchers or other researches, doubtful (improbable or contradictory) from the medicobiological point of view of results between researches or between the research centers);

critical dependence (reasons for efficiency and safety of drug, and also ratio of its advantage - risk) from results only of one research or researches on small selection of subjects;

medicine purpose for use by wide population of the population (for example, vaccines and other medicines which are intended for simultaneous use by big national groups);

high probability of emergence of ethical problems (participation in research of vulnerable national groups: children, persons with cognitive violations, patients with the diseases which do not have alternative therapy, the institutionalized patients, etc. according to requirements of the rules of proper clinical practice approved by the Commission);

conduct of clinical trial in clinical center of the geographical region where the level of requirements to conduct of clinical trials is lower established within the Union;

availability of data of authorized bodies of the states which are not members of the Union concerning problems with observance of requirements of proper clinical practice by the research center or the sponsor;

availability of the circumstances provided by the rules of conducting pharmaceutical inspections approved by the Commission.

In the presence of doubts concerning quality of medicine and drugs of comparison, including the placebos used in clinical trial the decision on conducting inspection (unplanned or planned) the production site of this medicine on compliance to requirements of proper production practice of the Union is made.

39. The decision on need of conducting unplanned inspection concerning results of researches of bioequivalence is passed by authorized body taking into account requirements of Items 37 and 38 of these rules based on complex assessment of the following factors:

a) submission of unreasonably homogeneous (heterogeneous) data of research of bioequivalence;

b) discrepancy of amount of the passed (dropping-out) values to expected values for this active ingredient or like measurements;

c) improbability (inconsistency) of the provided clinical, statistical or analytical data;

d) availability of contradictory results of researches concerning pharmacokinetic parameters or interindividual (intra individual) variability.

40. Unplanned inspection of system of pharmakonadzor of the holder of the registration certificate within the procedure of registration of medicine is carried out in the cases provided by the rules of proper practice of pharmakonadzor approved by the Commission.

IV. General principles of examination of medicines

41. Expertize of medicines is carried out for receipt of scientific quality evaluation, safety and efficiency of medicines and ratio "advantage - risk" medicines and can include:

a) assessment of the documents and data provided by the applicant in the registration file of medicine (file assessment);

b) laboratory testing on compliance to requirements of the regulating document for quality and verification of analytical techniques of quality control;

c) creation by the reference state of the expert report on medicine assessment;

d) assessment by the state of recognition of the expert report on assessment taking into account the documents and data containing in the registration file of medicine.

42. The basic principles of conducting examination of medicines in case of registration are:

a) independence and legal security of experts when implementing of professional activity by them;

b) obligation of fulfillment of requirements of the legislation of the state members, international treaties and acts constituting the right of the Union;

c) scientific approach, completeness, comprehensiveness and objectivity of researches of objects of examination, ensuring justification of results of examination according to documentary established eligibility criterions;

d) competence and high professional level of the expert organizations and experts;

e) systemacity of the organization of examination of medicines and its methodical providing;

e) orientation to world level of development of science and technology, regulation and rule of technical and public safety;

g) publicity of results of examination on condition of preserving the state, official and trade secret according to the legislation of state members, international treaties and acts constituting the right of the Union.

43. In case of development, performing preclinical (not clinical) and clinical trials (testing) of medicine, its production, implementation of pharmakonadzor and preparation of the documents provided for holding procedure of registration, registration confirmation (re-registration), modification of the registration file or other procedures connected with registration, developers, producers and holders of registration certificates of medicines and their authorized persons shall observe the legislation of state members, the international agreements and acts constituting the right of the Union and also to be guided by optimum approaches which realization will allow to provide accomplishment of such requirements and which are stated including in the decisions and recommendations accepted by the Commission. In case of non-compliance with the specified recommendations the applicant shall provide reasons for admissibility of the chosen approach from the point of view of quality assurance, efficiency and safety of medicine.

The provided reasons shall be estimated when conducting examination of medicines.

44. Examination of medicine is not interrupted for the term of conducting unplanned pharmaceutical inspections on compliance to requirements ought the practician of the Union (production, laboratory, clinical, pharmakonadzor), but the final expert report by assessment can be constituted by authorized body (the expert organization) of the reference state only taking into account results of unplanned pharmaceutical inspections (in case of their carrying out). The specified inspections shall be carried out in time, not exceeding 180 calendar days from acceptance date authorized body of the decision on initiation of inspection.

45. For the medicines requiring additional monitoring of safety according to requirements of proper practice of pharmakonadzor of the Union, general characteristic of medicine for medical application (further - OHLP) and the instruction on medical application of medicine the corresponding formulations and marks according to the requirements to the instruction on medical application of medicines and general characteristic of medicines for medical application approved by the Commission shall include (leaf insert) (further - the instruction on medical application).

V. Order of registration and examinations of medicines according to the procedure of mutual recognition

V.I. Registration and examination of medicine in the reference state

46. The term of carrying out registration and examination of medicine in the reference state shall not exceed 210 calendar days from the date of filing of application on registration of medicine till day of issue of the registration certificate.

47. For the purpose of medicine registration the applicant represents the following documents and materials to authorized body (the expert organization) of the reference state:

the statement on paper and (or) in the form of the electronic document in the established form according to appendix No. 2 to these rules;

the documents confirming payment of collection (duty) on registration and examination of medicine in the case and procedure established by the legislation of the reference state;

the registration file according to appendices No. No. 1 - 5 to these rules on the electronic medium (in addition the module of 1 registration file is represented on paper (except for the risk management plan, the main file (master file) of the production site (production sites) and the master file on pharmakonadzor));

samples of medicines.

The standard samples of active pharmaceutical substances and related impurity, specific reagents and other materials necessary for carrying out testing of samples of the medicines specified in paragraph five of this Item are represented in coordination with the expert organization.

Samples of medicines, specific reagents and other materials are represented in the quantities approved with the expert organization and necessary for carrying out no more than 3-fold analysis according to requirements of the regulating document for quality of medicines or other specifications which are the part of the registration file, in time, approved by authorized body (the expert organization), which is not entering aggregate term of examination and registration of medicine.

Representation of samples, specific reagents and other materials in case of impossibility of carrying out testing in the expert organization owing to inaccessibility of samples of medicines (including in case of their reference to category of the orphan, narcotic, psychotropic or intended for treatment highspending nozologiya owing to their high cost) is not required, to impossibility of observance of conditions of transportation of the specified samples on the territory of state member and (or) their storage, lack of the special equipment and consumable materials in the expert organization.

48. In the cases specified in paragraph eight of Item 47 of these rules, bench tests are carried out to laboratories of quality control of the producer of medicine in the presence of representatives of the expert organization or in the contractual laboratory used by the producer in the presence of representatives of the expert organization.

49. Examination of medicine in the reference state includes:

a) assessment of completeness, completeness and correctness of document creation, provided in the registration file;

b) assessment of the documents and data provided by the applicant in the registration file of medicine regarding safety, efficiency and quality;

c) laboratory testing on compliance to requirements of the regulating document for quality and reproducibility of the declared techniques of quality control performed in accredited test laboratories;

d) initiation in need of unplanned or planned pharmaceutical inspection in the cases established by these rules;

e) creation by the reference state of the expert report on medicine assessment.

50. The authorized body (the expert organization) of the reference state within 14 working days from the date of filing of application on registration performs assessment of completeness, completeness and correctness of document creation, provided in the registration file, to the direction of materials of the registration file on examination. No more than 90 calendar days which are not entering in time registration and examinations of medicine on representation of the materials lacking in the registration file according to notes of authorized body (the expert organization) of the reference state are provided to the applicant.

51. The authorized body (the expert organization) of the reference state rejects the registration application of medicine in case of non-presentation of materials of the registration file according to notes of authorized body (the expert organization) of the reference state and (or) non-confirmation of payment of collection (duty) on registration and examination of medicine in the cases and procedure established by the legislation of the reference state.

52. The authorized body and (or) the expert organization of the reference state when carrying out registration and (or) examination of medicine has the right to send to the applicant inquiry in written and (or) electronic type for provision of the missing additional information, necessary explanations or amendments of the documents and data provided in the registration file (including offers on modification of OHLP, the instruction on medical application, medicine packaging prototypes, the regulating documentation by quality or other documents of the registration file). After the first request the subsequent requests are allowed only in case of the additional questions concerning the data provided by the applicant in the response to prior request.

53. The term of submission by the applicant of the response to the request specified in Item 52 of these rules shall not exceed 90 calendar days from the date of receipt of request.

54. If necessary based on the corresponding reasons for the applicant the term established in Item 53 of these rules can be extended by authorized body (the expert organization) of the reference state. Aggregate term of reply to the requests shall not exceed 180 calendar days.

55. Time of submission of documents by the applicant at the request of authorized body or the expert organization in the course of examination of medicine does not enter conducting examination and registration of medicine in time.

56. In case of non-presentation by the applicant at the scheduled time of the requested documents and data examination and registration of medicine stop. The authorized body (the expert organization) informs the applicant in written and (or) electronic type within 14 working days from the date of adoption of this decision on the made decision.

57. Interaction of authorized bodies (the expert organizations) in case of the direction of requests to the applicant is performed in electronic form with use of the integrated system.

58. Examination of medicine in case of initiation of pharmaceutical inspection on compliance to proper pharmaceutical practicians of the Union does not stop. At the same time preparation of the expert report on assessment comes to the end with the reference state only after receipt of results of inspection by the expert organization of the reference state. Unplanned pharmaceutical inspection with the direction of the report on the carried-out inspection shall be carried out medicine registration, not exceeding 180 calendar days from acceptance date authorized body or the expert organization of the decision on initiation of conducting inspection in time.

The applicant will organize visit of the production site and (or) the research center and (or) inspection of system of pharmakonadzor of the holder of the registration certificate within 30 calendar days after receipt of information on need of conducting inspection or provides possible options of dates of visit, but no later than 90 calendar days after receipt of information on need of inspection.

59. For preparation of the expert report on assessment the expert organization of the reference state constitutes expert reports on aspects of quality, according to the new active ingredient containing in medicine according to the registration file on active ingredient, on preclinical, clinical aspects, the protocol of bench tests (if the expert organization carries out the corresponding testing) in forms according to appendices No. No. 6 - 10, 12 and 22 to these rules.

60. By results of medicine examination by the expert organization of the reference state the final expert report according to the medicine declared on registration including assessment of the explanations received from the applicant, documents and data provided in response to request of the expert organization or authorized body in form according to appendix No. 16 to these rules is constituted.

61. Expert reports on aspects of quality, preclinical, clinical aspects, the final expert report on assessment are constituted according to appendices No. No. 13 - 15 and 23to these rules.

62. The expert report on assessment shall be updated by the expert organization of the reference state in case of new information which is important for quality evaluation, safety or efficiency of medicine and can affect ratio "advantage - risk" medicine, within the procedure of modification of the registration file.

63. If by results of conducting examination of medicine by authorized body of the reference state the positive decision on medicine registration, the authorized body of the reference state in time which is not exceeding 10 working days is made:

a) issues to the applicant the registration certificate of medicine in form according to appendix No. 17 to these rules, the approved OHLP, the instruction on medical application, the regulating document on quality, prototypes of packagings, the expert report on assessment (if necessary the approved OHLP, the instruction on medical application and prototypes of packagings of medicine in state language of the reference state are issued to the applicant), the approved risk management plan (if necessary);

b) places data on medicine and the active pharmaceutical substances which are its part in the unified register with appendix of the approved OHLP, instructions on medical application, prototypes of packagings, the regulating document on quality, and also the final expert report by assessment constituted according to appendix No. 16 to these rules, after withdrawal of confidential data and data on experts, the approved risk management plan (if necessary) according to procedure for forming and maintaining the unified register.

64. The authorized body of the reference state refuses registration of medicine by results of conducting examination in the following cases:

a) the ratio of the expected advantage to the possible risks connected using medicine is not favorable;

b) efficiency of medicine is not confirmed with the data provided by the applicant;

c) quality of medicine is not confirmed;

d) the offered methods and techniques of quality control are not reproduced;

e) the applicant provides false information;

e) by results of the appointed inspection during registration of medicine compliance to proper pharmaceutical practicians of the Union is not confirmed.

65. In case of adoption by authorized body of the reference state of the decision on refusal in medicine registration the authorized body (the expert organization) of the reference state informs on it the applicant in electronic and (or) written type within 10 working days from the date of adoption of such decision.

V.II. Registration and examination of lekarstvennogopreparat according to the procedure of mutual recognition in the state (states) of recognition

66. The applicant after registration of medicine in the reference state can initiate according to the procedure of the procedure of mutual recognition registration in other state members chosen by the applicant as the states of recognition by submission to authorized bodies (the expert organization) of such state members:

registration applications of medicine according to the procedure of mutual recognition on paper and (or) in the form of the electronic document in form according to appendix No. 2 to these rules;

the documents confirming payment of collection (duty) on registration and examination of medicine in the case and procedure established by the legislation of the state of recognition;

the module of 1 registration file on paper and electronic carriers.

In the presence of relevant requirements in the legislation of state member OHLP, the instruction on medical application and prototypes of packagings of medicine in state language of the state of recognition are represented.

67. The authorized body (the expert organization) of the reference state at the request of the applicant in time which is not exceeding 5 working days from the date of receipt of this request provides access for authorized bodies (the expert organizations) of the states of recognition to the registration file of medicine and the expert report on assessment by means of the integrated system with use of the additional documents and data provided by the applicant on requests of authorized body (the expert organization) of the reference state.

68. Registration of medicine in the state of recognition in the absence of disagreements between authorized bodies of this state member and the reference state and availability of the conclusion about possibility of recognition of the expert report on assessment is performed no later than 90 calendar days from the date of receipt of access to the expert report on assessment.

69. Examination of medicine in case of the procedure of mutual recognition in the states of recognition is performed in the way:

a) considerations of the application, the documents and data provided in the registration file;

b) considerations of the expert report on assessment prepared by the expert organization of the reference state.

70. The authorized body (the expert organization) of the state of recognition within 14 working days from the date of filing of application rejects the registration application of medicine according to the procedure of mutual recognition in case of discrepancy of the statement to requirements of these rules and (or) non-confirmation of payment of collection (duty) on registration and examination of medicine in cases and procedure, stipulated by the legislation the states of recognition.

71. In case of registration of medicine by the procedure of mutual recognition the authorized body (the expert organization) of the state of recognition no later than 50 calendar days after receipt of access to the expert report on assessment in case of need sends inquiry to the applicant and to authorized body (the expert organization) of the reference state in form according to appendix No. 18 to these rules.

72. The applicant directs reply to the request to the authorized body (the expert organization) of the state of recognition in time which is not exceeding 90 calendar days. The term of the response of the applicant to request does not join in aggregate term of conducting examination and registration of medicine. The authorized body (the expert organization) of the state of recognition within 5 working days from the moment of receipt of the answer of the applicant provides to it access to authorized body (the expert organization) of the reference state by means of the integrated system.

73. In case of non-presentation at the scheduled time by the applicant requested by authorized body (the expert organization) of the state of recognition of documents and data, examination and registration of medicine in this state are derecognized.

74. The applicant is informed on the made decision of authorized body and (or) expert organization (in electronic and (or) paper type) within 10 working days from the date of decision making.

75. The authorized body (the expert organization) of the state of recognition by results of conducting examination of medicine in time which is not exceeding 50 calendar days from the date of giving to the state of recognition of the registration application of medicine (in the absence of requests to the applicant), or in time, not exceeding 20 calendar days from the date of receipt of the response of the applicant to the inquiry sent by authorized body (the expert organization) of the state of recognition, with use of the integrated system sends to authorized body (the expert organization) of the reference state the conclusion about opportunity or impossibility of recognition of the expert report on assessment prepared by the reference state. The authorized body of the reference state brings the received decision to the attention of the applicant.

76. If by results of conducting examination of medicine by authorized body of the state of recognition the positive decision on medicine registration, authorized body of the state of recognition no later than 10 working days is made:

a) issues to the applicant the registration certificate of medicine in form according to appendix No. 17 to these rules, and also the approved OHLP, the instruction on medical application, prototypes of packagings in state language of the state of recognition in the presence of relevant requirements in the legislation of the state of recognition;

b) approves the regulating document on quality issued by the reference state;

c) places data on medicine and the active pharmaceutical substances which are its part in the unified register with appendix of the approved OHLP, instructions on medical application, prototypes of packagings, the approved risk management plan (if necessary) according to procedure for forming and maintaining the unified register.

77. The registration certificate of medicine is issued by authorized body of the state of recognition with the effective period of the registration certificate established by the reference state.

78. Registration of the medicine registered according to these rules in other state members which are not specified in primary registration application as the states of recognition and also in the states which joined the Union after medicine registration is performed according to the procedure of mutual recognition on the basis of consideration of urgent edition of the expert report on assessment prepared by the expert organization of the reference state.

79. In case of impossibility of recognition of the expert report on assessment prepared by the expert organization of the reference state, the authorized body (the expert organization) of the state of recognition sends to authorized body (the expert organization) of the reference state, other states of recognition participating in the procedure of registration of medicine, to the applicant and in Expert committee the conclusion about impossibility of recognition of the given expert account on assessment with indication of the following reasons:

a) the attitude of the expected advantage towards the possible risks connected using medicine is not favorable;

b) the applicant does not prove efficiency of medicine;

c) quality of medicine is not confirmed;

d) the applicant provides false information;

e) by results of the appointed inspection during registration of medicine the discrepancy to proper pharmaceutical practicians of the Union which is critical is revealed.

80. The expert committee in time which is not exceeding 60 calendar days from the date of receipt of the conclusion of authorized body of the state of recognition about impossibility of recognition of the expert report on assessment prepared by the expert organization of the reference state performs the procedure of consideration of disagreements according to the procedure established by the Commission.

81. The authorized body of the state of recognition refuses medicine registration if by results of examination of medicine and after holding procedure of settlement of disagreements in Expert committee it makes the decision that the data provided in the expert report on assessment cannot be acknowledged sufficient for confirmation of quality and (or) efficiency, and (or) favorable ratio "advantage - risk" medicine.

82. In case of availability of disagreements of authorized bodies regarding recognition of the expert report on assessment and their consideration by Expert committee the authorized body of the state of recognition which made the positive decision on recognition of the expert report on assessment prepared by the expert organization of the reference state issues the registration certificate, the approved OHLP, the instruction on medical application, prototypes of packagings and approves the risk management plan (if necessary), the regulating document on quality to the decision of Expert committee. At the request of the applicant issue of the registration certificate by authorized body of such state of recognition can be suspended before elimination of disagreements of authorized bodies of other states of recognition and the reference state.

The registration certificate issued in such cases acts on the territory of this state of recognition.

VI. Order of registration and examinations according to the decentralized procedure in the reference state and the states of recognition

83. For the purpose of registration of medicine according to the decentralized procedure the applicant chooses the reference state and the states of recognition.

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