Decision of the Council of the Eurasian Economic Commission dated 03.11.2016 N 78 (as amended on 20.10.2023)
"On the Rules for the Registration and Expertise of Medicines for Medical Use"
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Note to the document
The version comes into effect on 20.12.2023.
The amendments introduced by the Decision of the EEC Council dated 20.10.2023 N 114 (as amended on 24.11.2023) entered into force on 20 December 2023.
Document title
Decision of the Council of the Eurasian Economic Commission dated 03.11.2016 N 78
(as amended on 20.10.2023)
"On the Rules for Registration and Expertise of Medicines for Medical Use"
COUNCIL OF THE EURASIAN ECONOMIC COMMISSION
DECISION
of November 3, 2016 N 78
ON THE RULES
OF REGISTRATION AND EXPERTISE OF MEDICINES
FOR MEDICAL USE
List of amending documents
(as amended by decisions of the Council of the Eurasian Economic Commission
dated 14.06.2018 N 55, dated 30.01.2020 N 9, dated 23.12.2020 N 128,
dated 05.03.2021 N 14, dated 23.04.2021 N 34, dated 17.03.2022 N 36,
dated 23.09.2022 N 141, dated 22.05.2023 N 60, dated 20.10.2023 N 114
In accordance with Article 7 of the Agreement on Uniform Principles and Rules for the Circulation of Medicines within the Eurasian Economic Union dated December 23, 2014, paragraph 84 of Appendix No. 1 to the Regulations of the Eurasian Economic Commission, approved by Decision of the Supreme Eurasian Economic Council dated December 23, 2014 No. 98, and Decision of the Supreme Eurasian Economic Council dated December 23, 2014 No. 108 "On the implementation of the Agreement on Uniform Principles and Rules for the Circulation of Medicines within the Eurasian Economic Union", the Council of the Eurasian Economic Commission decided:
a) registration, confirmation of registration (re-registration), amendments to the registration dossier and other procedures related to the registration of medicinal products for medical use, stipulated by the legislation of the Member States of the Eurasian Economic Union (hereinafter referred to as the Member States, the Union) and not completed by the authorized bodies of the Member States before January 1, 2016, shall be carried out in accordance with the legislation of the Member States;
b) until July 1, 2021 (in the Russian Federation - until December 31, 2020), at the applicant's discretion, registration of a medicinal product may be carried out either in accordance with the Rules or in accordance with the legislation of a Member State. In this case, medicinal products registered in accordance with the legislation of a Member State are allowed to circulate only in the territory of the Member State whose authorized body issued the registration certificate;
(as amended by the decision of the Council of the Eurasian Economic Commission dated 23.12.2020 N 128)
c) the validity of registration certificates of medicinal products submitted for registration (expert work for the purpose of registration) in accordance with the legislation of the Member States before July 1, 2021, may be extended in accordance with the legislation of the Member States, but not later than until December 31, 2025. At the same time, changes to the registration dossiers of such medicinal products, formed in accordance with the legislation of the Member States, are carried out in accordance with the legislation of the Member States no later than December 31, 2025;
(as amended by decisions of the Council of the Eurasian Economic Commission of 23.12.2020 N 128, of 05.03.2021 N 14)
d) medicinal products registered in accordance with the legislation of the Member States must be brought into compliance with the requirements of international treaties and acts constituting the law of the Union by December 31, 2025;
e) registration certificates of medicinal products issued in accordance with the legislation of the Member States are valid until their expiration date, but not later than December 31, 2025.
3. Member States, by December 31, 2016:
a) approve the amount of fees (duties) or other mandatory payments provided for by the Rules, taking into account the complexity of the procedures and the volume of work performed in the reference state and the states of recognition, including during:
registration of a medicinal product;
confirmation of registration (re-registration) of a medicinal product;
bringing the registration dossier of a medicinal product into line with the requirements of international treaties and acts constituting the law of the Union;
b) determine the bodies (organizations) authorized to carry out registration, confirmation of registration (re-registration), amendments to the registration dossier and other procedures related to the registration of medicinal products for medical use provided for by the Rules, and inform the Eurasian Economic Commission thereof.
4. This Decision shall enter into force after 10 calendar days from the date of entry into force of the Protocol signed on December 2, 2015, on the accession of the Republic of Armenia to the Agreement on uniform principles and rules for the circulation of medicines within the Eurasian Economic Union dated December 23, 2014, but not earlier than after 10 calendar days from the date of official publication of this Decision.
Members of the Council of the Eurasian Economic Commission:
From the Republic of Armenia
V. GABRIELYAN 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 the Council
of the Eurasian Economic Commission
dated November 3, 2016 N 78
RULES FOR REGISTRATION AND EXPERTISE OF MEDICINES FOR MEDICAL USE
dated 14.06.2018 N 55, dated 30.01.2020 N 9, dated 05.03.2021 N 14,
dated 23.04.2021 N 34, dated 17.03.2022 N 36, dated 23.09.2022 N 141,
dated 22.05.2023 N 60, dated 20.10.2023 N 114
I. General Provisions
1. These Rules determine the procedure for registration, confirmation of registration (re-registration), amendments to the registration dossier and examination of medicinal products for medical use in order to form a common market for medicinal products within the Eurasian Economic Union (hereinafter referred to as the Union), as well as other procedures related to the registration of medicinal products for medical use (hereinafter referred to as registration-related procedures), including:
a) bringing the registration dossier of a medicinal product registered under the national procedure in the Member States of the Union (hereinafter referred to as the Member States) into compliance with these Rules (hereinafter referred to as bringing into compliance with the requirements of the Union);
(subparagraph "a" as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 N 114)
b) suspension and cancellation of registration of medicinal products or restriction of the use of a medicinal product;
c) issuance of duplicates of the registration certificate of a medicinal product.
2. The requirements of these Rules shall apply to developers and manufacturers of medicinal products, holders of registration certificates for medicinal products, their authorized representatives, and authorized bodies (expert organizations) of the Member States in the field of circulation of medicinal products.
3. The requirements of these Rules shall not apply to:
a) medicinal products that are intended for use in military operations, emergency situations, for the prevention and treatment of diseases and injuries resulting from exposure to chemical, biological, and radiation factors, developed on the instructions of state authorities of the Member States authorized in the field of security and defense, and the circulation of which is regulated by the legislation of the Member States;
a) medicinal products that are intended for use in emergency situations, the threat of their occurrence or the occurrence of emergency situations, for the prevention and treatment of diseases and injuries that pose a danger to others, resulting from exposure to chemical, biological, and radiation factors, the circulation of which is regulated by the legislation of the Member States;
(paragraph "a.1" introduced by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
b) veterinary medicinal products, the circulation of which is regulated by other acts that are part of the law of the Union.
4. Medicinal products intended for circulation on the common market of medicinal products within the Union or on the territory of one of the Member States are subject to registration in accordance with these Rules.
5. The following are not subject to registration within the Union:
a) medicinal products manufactured in pharmacies;
b) pharmaceutical substances;
c) medicinal products intended for preclinical and clinical trials;
d) medicinal products imported by individuals for personal use;
e) radiopharmaceutical medicinal products manufactured directly in medical organizations in the manner established by the authorized bodies of the Member States;
(as amended by the Decision of the Council of the Eurasian Economic Commission of 17.03.2022 N 36)
f) medicinal products not intended for sale in the customs territory of the Union;
g) samples of medicinal products intended for registration and standard samples;
h) medicinal products intended for use as exhibition samples.
5.1. In the cases and in the manner stipulated by the legislation of the Member States, it is allowed to provide patients with and use them with unregistered medicinal products. Such medicinal products include, among other things:
medicines imported into a Member State to provide medical care for vital indications of a specific patient or to provide medical care to a limited group of patients with a rare and (or) particularly severe pathology, on the basis of a conclusion (permit document) issued by the authorized body of the Member State;
high-tech medicinal products manufactured on a non-standardized (non-routine) basis and used in the territory of the same Member State in a hospital for the purpose of fulfilling an individual medical prescription for a medicinal product specially produced for an individual patient.
(as amended by the decision of the Council of the Eurasian Economic Commission of 22.05.2023 N 60)
The production of such high-tech medicinal products is permitted by the authorized body of the Member State. Member States are obliged to ensure the equivalence of the requirements for the traceability of series and batches of medicinal products established by the legislation of the Member States and for pharmacovigilance in accordance with the acts of the Union bodies.
(as amended by the decision of the Council of the Eurasian Economic Commission dated 22.05.2023 N 60)
(clause 5.1 introduced by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
6. If a medicinal product is recognized as an orphan drug in the territories of all or several Member States in accordance with the legislation of the Member States, such medicinal product shall be registered in accordance with Sections V and VII or Sections VI and VII of these Rules, as well as in accordance with the requirements of Section 16 of Part III of Appendix No. 1 to these Rules.
If a medicinal product is not recognized as an orphan drug in the territory of any Member State in accordance with the legislation of that State, such medicinal product shall be registered in that State in accordance with the requirements of Subsection I of Section V of these Rules and Appendix No. 1 to these Rules.
If a medicinal product is intended for the treatment of an orphan disease included in the lists maintained in accordance with the legislation of an individual Member State, the registration of such medicinal product in the reference State in accordance with these Rules for the purpose of placing the medicinal product on the market of that State only (national registration procedure) shall be carried out in accordance with Sections V and VII or Sections VI and VII of these Rules, as well as in accordance with the provisions of Section 16 of Part III of Appendix No. 1 to these Rules.
(paragraph introduced by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No. 36)
7. It is prohibited to register medicinal products with different qualitative compositions of active substances under one trade name.
8. It is permitted to register one medicinal product with different trade names in different Member States in the following cases:
a) the use of the proposed trade name may be contrary to legal and moral norms or otherwise does not take into account national cultural and (or) linguistic characteristics;
b) the intellectual property rights to the trade name in the form of a trademark belong to a person other than the person who submitted the application for registration of the medicinal product (hereinafter referred to as the applicant) or the holder of the registration certificate, and the applicant or the holder of the registration certificate cannot provide a corresponding license agreement granting the right to use the trademark;
c) the medicinal product was registered under different trade names in accordance with the legislation of the Member States before December 31, 2020.
9. Registration of a medicinal product, confirmation of registration (re-registration), amendments to the registration dossier, as well as procedures related to registration, are carried out by authorized bodies.
10. The examination of the medicinal product shall be carried out by an expert organization determined in accordance with the legislation of the Member State.
11. The authorized bodies and expert organizations shall ensure the confidentiality of the information contained in the registration dossier of the medicinal product in the process of registration and examination of medicinal products, including the information contained in the closed part of the master file for the active pharmaceutical substance.
The Eurasian Economic Commission (hereinafter referred to as the Commission) and the Expert Committee on Medicines (hereinafter referred to as the Expert Committee) shall ensure the confidentiality of the information contained in the registration dossier of the medicinal product obtained in the course of their activities.
12. The applicant, in accordance with the legislation of the Member State, shall bear the costs of registration, confirmation of registration (re-registration), amendments to the registration dossier and examination of medicinal products, procedures related to registration, as well as for conducting inspections to determine compliance with the requirements of good pharmaceutical practices initiated in connection with the implementation of the said procedures.
13. The applicant shall not be reimbursed for the expenses specified in paragraph 12 of these Rules, except in cases where the applicant submits an application to withdraw an application for registration, confirmation of registration (re-registration), amendments to the registration dossier of a medicinal product prior to the start of the examination (issuance of an assignment for the examination or conclusion of an agreement for the examination) or other cases stipulated by the legislation of the Member States.
(paragraph 13 as amended by the decision of the Council of the Eurasian Economic Commission dated 05.03.2021 N 14)
14. The authorized body (expert organization) of the reference state, upon receipt of an application for registration, confirmation of registration (re-registration), amendments to the registration dossier and procedures related to registration, assigns it a unique number generated using the integrated information system of the Union (hereinafter referred to as the integrated system), and communicates it to the applicant.
15. The authorized body (expert organization) of a Member State shall submit information related to the implementation of registration, confirmation of registration (re-registration), amendments to the registration dossier, as well as procedures related to registration, to the authorized bodies (expert organizations) of other Member States, as well as to the Commission using the integrated system by the application number in accordance with the procedure for the formation and maintenance of a single register of registered medicines of the Union (hereinafter referred to as the single register).
(as amended by the decision of the Council of the Eurasian Economic Commission dated 05.03.2021 N 14)
The authorized body (expert organization) of the reference state, no later than 5 working days from the date of submission of the registration dossier by the applicant in electronic form, provides access to the information in the registration dossier at the request of the authorized bodies (expert organizations) of the states of recognition through the use of the integrated system.
If the Commission needs to provide access to a regulatory document on the quality of a medicinal product using the integrated system, the authorized bodies (expert organizations) of the Member States shall send a corresponding written request to the Commission containing information on the laboratories implementing quality control and the experts who need to be granted such access.
(paragraph introduced by the decision of the Council of the Eurasian Economic Commission of 22.05.2023 N 60)
If it is necessary to restrict access to a regulatory document on quality previously provided by the Commission, the authorized bodies (expert organizations) of the Member States shall send a corresponding written request to the Commission indicating information on the laboratories implementing quality control and the experts whose access to the document needs to be restricted.
16. Based on the results of registration of a medicinal product, the authorized body of each Member State that has registered the medicinal product shall issue a registration certificate for the medicinal product confirming the fact of its registration.
17. The registration certificate of a medicinal product shall be issued in a uniform form and in accordance with the rules for filling out the registration certificate of a medicinal product for medical use in accordance with Appendix No. 17 to these Rules by the authorized body that registered the medicinal product.
In case of loss or damage of the registration certificate of a medicinal product, at the request of the holder of the registration certificate for the issuance of a duplicate of the registration certificate of the medicinal product, the authorized body that issued this registration certificate shall issue a duplicate thereof, executed in accordance with the rules for completion according to Appendix No. 17 to these Rules.
18. The validity period of the registration certificate for a medicinal product registered for the first time in the reference state is 5 years. Upon expiration of the specified period, an indefinite registration certificate of the medicinal product shall be issued, subject to confirmation of its registration (re-registration). In cases related to pharmacovigilance issues, the authorized body may re-issue the registration certificate with a validity period of 5 years based on the results of confirmation of registration (re-registration).
(as amended by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
The validity period of the registration certificate for a medicinal product registered under the conditional registration procedure is determined taking into account the provisions of subsection VII.III of section VII of these Rules.
(paragraph introduced by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
For a medicinal product registered in accordance with the legislation of a member state for 5 years or more, an unlimited registration certificate is issued if the medicinal product is intended to be circulated on the market of only that member state.
(as amended by the decision of the Council of the Eurasian Economic Commission of 20.10.2023 N 114)
A registration certificate for a medicinal product registered in accordance with the legislation of the Member States specified in the application for bringing it into compliance with the requirements of the Union and registered for 5 years or more on the market of the reference state shall be issued for an unlimited period as part of the procedure for bringing it into compliance with the requirements of the Union in accordance with Section XIII of these Rules.
In this case, in the cases specified in paragraphs three and four of this clause, as part of the procedure for bringing it into compliance with the requirements of the Union, the authorized body (expert organization) of the reference state may establish one or more additional requirements in accordance with paragraph 116 of these Rules, and in such a case a registration certificate shall be issued with a validity period of 5 years.
(paragraph introduced by decision of the Council of the Eurasian Economic Commission dated 20.10.2023 N 114)
II. Definitions
19. For the purposes of these Rules, the following concepts are used:
"allergen" - any medicinal product intended to identify or induce a specific acquired change in the immunological response to a substance that causes an allergy;
"safety of a medicinal product (benefit-risk ratio)" - an assessment of the positive therapeutic effects of a medicinal product in relation to the risks associated with its use (the concept of risk includes any risk associated with the quality, safety or effectiveness of a medicinal product in relation to the health of a patient or the population);
"biosimilar medicinal product (bioanalogue, biosimilar medicinal product, biosimilar)" - a biological medicinal product that contains a version of the active substance of a registered biological original (reference) drug and for which similarity (similarity) has been demonstrated on the basis of comparative studies with the reference drug in terms of quality, biological activity, efficacy and safety; "biological availability (bioavailability)" - the rate and extent to which the active substance or its active part of the molecule from the dosage form is absorbed and becomes available at the site of action;
"biological equivalence (bioequivalence)" - the absence of significant differences in the rate and extent to which the active substance or active moiety of the active substance molecule of pharmaceutical equivalents or pharmaceutical alternatives becomes available at its site of action when administered at the same molar dose under similar conditions in a properly designed study;
"biological medicinal product" - a medicinal product whose active substance is produced or isolated from a biological source and for the description of the properties and quality control of which a combination of biological and physicochemical methods of analysis with an assessment of the production process and methods for its control is necessary;
"generic medicinal product" - a medicinal product that has the same quantitative and qualitative composition of active substances and the same dosage form as the original medicinal product, and whose bioequivalence to the original medicinal product is confirmed by appropriate bioavailability studies. Different salts, esters, isomers, mixtures of isomers, complexes or derivatives of an active substance are considered to be the same active substance if their safety and efficacy do not differ significantly. Different immediate-release oral dosage forms are considered to be the same dosage form for the purposes of bioavailability studies;
"radionuclide generator" - any system containing a fixed primary radionuclide from which secondary radionuclides are formed, which are extracted by elution or other means and used in a radiopharmaceutical medicinal product;
"hybrid medicinal product" - a medicinal product that does not fall under the definition of a generic medicinal product if its bioequivalence cannot be confirmed using bioavailability studies, and also if the active substance(s), indications for use, dosage, dosage form or route of administration have changed in this medicinal product compared to the original medicinal product;
"homeopathic medicinal product" - a medicinal product manufactured using homeopathic technology using homeopathic raw materials in accordance with the requirements of the Pharmacopoeia of the Union or, in their absence, in accordance with the requirements of homeopathic pharmacopeias;
"state of recognition" - a member state in which a medicinal product is registered (is registered) with an examination, including an assessment of the expert report on the assessment of the safety, efficacy and quality of the medicinal product prepared by the reference state;
"data from real clinical practice" - data related to the patient's health status and (or) the process of providing medical care, obtained from various sources;
(paragraph introduced by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
"holder of the registration certificate" - a legal entity in whose name the registration certificate for a medicinal product has been issued and which is responsible for the safety, efficacy and quality of the medicinal product;
"evidence obtained on the basis of real clinical practice data" - clinical evidence regarding the use and potential benefit or risk of using a medicinal product, obtained on the basis of collecting and analyzing real clinical practice data;
"unified register of registered medicinal products of the Union" - a common information resource formed within the framework of an integrated system and containing information on medicinal products registered or having undergone other procedures related to registration in accordance with these Rules;
"applicant" - a legal entity authorized to submit an application for registration, confirmation of registration (re-registration), amendments to the registration dossier of medicinal products, other procedures related to registration, and responsible for the accuracy of the information contained in the documents submitted by it and the data of the registration dossier;
"immunological medicinal product (immunobiological medicinal product)" - a medicinal product intended to form active or passive immunity, or to diagnose the presence of immunity, or to diagnose (develop) a specific acquired change in the immunological response to allergenic substances;
"instructions for medical use (package insert)" - a document approved by the authorized body of a member state in accordance with the acts of the Union bodies, containing information for the consumer and accompanying the medicinal product in the package;
"quality of a medicinal product" - a set of properties and characteristics of a pharmaceutical substance and a medicinal product, ensuring their compliance with the intended purpose in accordance with the requirements of the acts of the Union bodies;
"critical remark" - an expert's remark that the data submitted in the registration dossier by the applicant do not confirm the quality and (or) effectiveness of the registered medicinal product for medical use or indicate that the benefit-risk ratio for the medicinal product is unacceptable and the risk of harm to human health due to taking the medicinal product exceeds the effectiveness of using such a medicinal product, which makes its registration impossible;
(paragraph introduced by Decision of the Council of the Eurasian Economic Commission dated 22.05.2023 N 60)
"dosage form" - the state of a medicinal product corresponding to the methods of its administration and use and ensuring the achievement of the desired effect;
"medicinal plant materials" - fresh or dried plants, algae, fungi or lichens, or parts thereof, whole or crushed, used for the production of medicinal products;
"a medicinal product with well-studied medical use" - a medicinal product whose active substance has been well studied in the course of medical use, while its efficacy and acceptable degree of safety are recognized, confirmed by detailed bibliographic references to published data on post-registration and (or) epidemiological studies, and at least 10 years have passed from the date of the first systematic and documented use of the active substance (active substances) of this medicinal product in at least 3 Member States;
"herbal medicinal product" - a medicinal product containing as active components exclusively medicinal plant materials and (or) herbal pharmaceutical substance (substances);
"international nonproprietary name" - the name of the active substance recommended by the World Health Organization;
"minor remark" - an expert's remark that the documents submitted in the registration dossier on the quality, safety and efficacy of a medicinal product deviate from the requirements of the relevant acts of the Union bodies in the field of circulation of medicinal products, which cannot lead to a risk of harm to human health due to taking the medicinal product;
(paragraph introduced by the decision of the Council of the Eurasian Economic Commission dated 22.05.2023 N 60)
"normative document on quality" - a document that establishes requirements for the quality control of a medicinal product (containing a specification and description of analytical methods and tests or references to them, as well as the relevant acceptance criteria for the specified quality indicators, etc.) based on the conducted examination of the medicinal product, approved by the authorized body upon registration, confirmation of registration (re-registration), amendments to the registration dossier and bringing the registration dossier into line with the requirements of the Union and is intended to control the quality of the medicinal product in the post-registration period on the territory of the Union;
(as amended by the decision of the Council of the Eurasian Economic Commission of 23.04.2021 N 34)
"general characteristics of a medicinal product" - a document approved by the authorized body of a member state, in accordance with acts of the Union bodies, containing information for healthcare professionals on the safe and effective use of a medicinal product;
"common (group) name" - the name of a medicinal product that does not have an international nonproprietary name, or a combination of medicinal products, used to combine them into a group under a single name based on the same qualitative composition of active ingredients;
"original medicinal product" - a medicinal product with a new active ingredient, which was the first to be registered and placed on the world pharmaceutical market on the basis of a dossier containing the results of full preclinical (non-clinical) and clinical studies confirming its quality, safety and effectiveness;
"orphan (rare) medicinal product" - a medicinal product intended for diagnostics, etiopathogenetic or pathogenetic treatment (treatment aimed at the mechanism of disease development) of rare (orphan) diseases, the incidence of which does not exceed the officially determined level in the Member State;
"representative of the holder of the registration certificate" - a legal entity registered in accordance with the legislation of the Member State, or a separate subdivision of a legal entity located in the territory of the Member State and authorized by the holder of the registration certificate to perform actions related to the circulation of medicinal products in the territory of the Member State;
"manufacturer of medicinal products" - an organization carrying out activities for the production of medicinal products and having a permit (license) for such activity, issued by the authorized body of the manufacturing country;
"radiopharmaceutical medicinal product" - a medicinal product containing in a ready-to-use state one or more radionuclides (radioactive isotopes) as an active substance or as part of the active substance;
"plant pharmaceutical substance" - a product obtained from medicinal plant raw materials as a result of stages of the production process using such methods as extraction, distillation, pressing, fractionation, purification, concentration, fermentation, as well as grinding of medicinal plant raw materials to a given degree. Such substances include tinctures, extracts, essential oils, squeezed juices and processed extracts, medicinal plant raw materials ground to a given degree or powdered. Such substances do not include whole medicinal plant raw materials, as well as medicinal plant raw materials subjected to mechanical processing by the manufacturer (cutting, grinding, pressing, sifting, separation, etc.); (as amended by Decision of the Council of the Eurasian Economic Commission dated 22.05.2023 N 60)
"registration dossier" - a set of documents (including an application), executed in accordance with these Rules, submitted for carrying out procedures related to the registration, confirmation of registration (re-registration) of a medicinal product;
"registration certificate of a medicinal product" - a document of a uniform form issued by an authorized body, confirming the fact of registration of a medicinal product and constituting permission for its medical use in the territory of a member state;
"registration number" - a code designation assigned to a medicinal product upon registration in the territory of a member state;
"registration of a medicinal product" - the process of obtaining permission for medical use of a medicinal product in the territories of one or more member states, carried out in accordance with these Rules;
"reference state" - a member state that prepares an expert report on the assessment of the safety, efficacy and quality of a medicinal product based on an examination of the medicinal product in accordance with these Rules;
"reference medicinal product" - a medicinal product that is used as a comparison drug and is a standard by which the properties of a medicinal product are determined (standardized);
"risks associated with the use of a medicinal product" - any risks associated with the quality, safety or efficacy of a medicinal product in relation to the health of patients or the population, or risks leading to an undesirable impact on the environment;
"specification" - a list of quality indicators, references to analytical methods and tests and standards that represent numerical (quantitative) limits, ranges and other criteria for the specified quality indicators;
"standard sample" - an identified homogeneous substance or mixture of substances intended for use in chemical, physical and biological studies in which its properties are compared with the properties of the medicinal product under study, and possessing a degree of purity sufficient for the appropriate use;
"trade name of a medicinal product" - the name under which a medicinal product is registered;
"pharmaceutical substance (active pharmaceutical substance)" - a medicinal product intended for the production and manufacture of medicinal products;
"expert report on the assessment of safety, efficacy and quality (expert assessment report)" - a document containing the results of the examination of the safety, efficacy and quality of a medicinal product and a conclusion on the possibility (or impossibility) of its registration, confirmation of registration (re-registration), amendments to the registration dossier, bringing it into compliance with the requirements of the Union, prepared by an expert organization of the reference state;
"efficacy of a medicinal product" - a set of characteristics that ensure the achievement of a prophylactic, diagnostic or therapeutic effect or the restoration, correction or modification of a physiological function.
III. General principles of registration of medicinal products
20. Registration of medicinal products may be carried out at the request of the applicant in accordance with the mutual recognition procedure or the decentralized registration procedure.
(as amended by the decision of the Council of the Eurasian Economic Commission of 17.03.2022 N 36)
21. The mutual recognition procedure is carried out:
a) by the reference state in accordance with these Rules for the purpose of circulation of the medicinal product on the market of this state only (national registration procedure);
b) in the states of recognition - at the request of the applicant after registration of the medicinal product in the reference state under the mutual recognition procedure. Simultaneous initiation of the mutual recognition procedure in several recognition states is allowed.
22. The decentralized registration procedure is carried out simultaneously by several Member States to which an application for registration of a medicinal product has been submitted, with the choice of the reference state.
23. The applicant shall independently select the reference state and, if necessary, the state of recognition when submitting an application for registration of a medicinal product.
The applicant has the right to withdraw his/her application at any time before the end of the registration procedure for a medicinal product by notifying in writing the authorized body of the member state where the application is being considered of the withdrawal.
(paragraph introduced by the decision of the Council of the Eurasian Economic Commission dated 05.03.2021 N 14)
In the event of withdrawal of the application, the authorized body of the member state where the application is being considered shall cease its consideration on the merits and return to the applicant the originals of the documents and (or) information submitted with the application.
24. Only one state may act as a reference state.
25. The requirements for the documents and data of the registration dossier in the format of a general technical document submitted for registration of a medicinal product are established by Appendices No. 1 - 5 to these Rules.
26. Prior to filing an application for registration of a medicinal product, authorized bodies or expert organizations of the Member States may, at the request of the applicant, conduct scientific and pre-registration consultations in accordance with the legislation of the Member States, on issues related to the conduct of analytical tests, preclinical and clinical studies (trials), aspects of the registration procedure, including issues related to the qualification, type of application for registration of a medicinal product in order to determine the volume of documents and data of the registration dossier, with respect to the completeness of the registration dossier, the format for submitting the application and registration dossier, the need to provide samples of the medicinal product, standard samples, materials, specific reagents, consumables necessary for conducting a laboratory examination of quality in the expert organization or as designated by it, and on other issues.
27. In the event that, during the registration procedures, confirmation of registration (re-registration), amendments to the registration dossier or procedures related to registration, the authorized body or expert organization of the reference state identifies facts that cast doubt on the reliability of the information provided by the applicant in the registration dossier in relation to the preclinical (non-clinical) studies (trials) of medicinal products and clinical studies (trials) of medicinal products or the production of a medicinal product, including the production of a pharmaceutical substance or the organization of a pharmacovigilance system, the pharmaceutical inspectorate of this state shall initiate an inspection for compliance with the requirements of the relevant good pharmaceutical practices. Such inspections may also be initiated in the cases specified in paragraphs 31, 33, 35, 37 - 39 of these Rules. The responsibility for the timely initiation of relevant unscheduled inspections, if necessary, lies with the authorized body of the reference state.
28. The production of medicinal products must comply with the Rules of Good Manufacturing Practice of the Eurasian Economic Union.
29. When submitting an application for registration, confirmation of registration (re-registration), or bringing a medicinal product into compliance with the Union requirements, the applicant must submit as part of the registration dossier a valid document confirming compliance with the Union good manufacturing practice requirements, the manufacturing site (manufacturing sites) producing the finished dosage form and issuing quality control of the medicinal product submitted for registration, confirmation of registration (re-registration), or bringing it into compliance with the Union requirements.
With respect to the manufacturing site (manufacturing sites) of the medicinal product, the applicant, instead of a document confirming compliance with the Union good manufacturing practice requirements, has the right to submit, before the expiration of its validity, a document confirming compliance with the good manufacturing practice requirements issued to the manufacturer of the medicinal product by the authorized body of the Member States, the manufacturing site (manufacturing sites) of the medicinal product producing the finished dosage form and issuing quality control.
(as amended by decisions of the Council of the Eurasian Economic Commission of 14.06.2018 N 55, of 23.04.2021 N 34)
30. If it is impossible to submit a valid document confirming the compliance of the production site (production sites) of the medicinal product with the requirements of good manufacturing practice of the Union, the applicant, when submitting an application for registration of the medicinal product or for bringing it into compliance with the requirements of the Union before December 31, 2024, instead of this document, shall submit the following documents and information:
(as amended by decisions of the Council of the Eurasian Economic Commission of 14.06.2018 N 55, of 23.04.2021 N 34, of 22.05.2023 N 60)
a) valid documents confirming the compliance of the production site (production sites) carrying out the production of the finished dosage form and the release quality control of the medicinal product with the requirements of good manufacturing practice, issued to the manufacturer of the medicinal product by an authorized body of the country - manufacturer of the medicinal product;
b) a copy of the report on the results of the last inspection of the production site (production sites at the production stages), carried out by the authorized body of the country of manufacture and (or) another authorized body over the past 3 years;
c) information on the results of all inspections of this production site (production sites) for compliance with the requirements of good manufacturing practice, carried out over the past 3 years;
d) information on complaints regarding the quality of medicinal products manufactured at this production site (production sites), over the past 3 years;
d) consent to conduct a pharmaceutical inspection for compliance with the requirements of good manufacturing practice of the Union;
e) a copy of the main dossier (master file) of the production site (production sites).
31. The reference state, on the basis of the documents submitted by the applicant, specified in paragraph 30 of these Rules, taking into account the assessment of possible risks, makes a decision on the need to conduct an unscheduled pharmaceutical inspection for compliance with the requirements of good manufacturing practice of the Union during the registration procedures for the medicinal product or on the inclusion of an inspection of the production site (production sites) where the medicinal product applied for registration or for bringing into compliance with the requirements of the Union is manufactured, including, if necessary, the pharmaceutical substance, in the plan for conducting inspections in the first 3 years after completion of the registration procedures.
32. In the event of documentary justification by the authorized body of the reference state of the impossibility of conducting an unscheduled inspection of the production site (production sites) of the medicinal product by the reference state during the registration procedures for the medicinal product, the applicant has the right, in agreement with the reference state, to apply to one of the Member States with an application for an inspection of this production site (production sites) for compliance with the requirements of good manufacturing practice of the Union. In the event of a written refusal by the authorized bodies of the recognition states to conduct an unscheduled inspection of the production site(s) of the medicinal product, the authorized body of the reference state is obliged to organize and conduct an unscheduled inspection within the timeframe for conducting registration procedures in relation to the medicinal product.
33. The decision on the need to conduct an unscheduled pharmaceutical inspection for compliance with the requirements of good manufacturing practice of the Union shall be made by the authorized body of the reference state in the process of implementing:
a) the registration procedure - for medicinal products manufactured at sites that manufacture finished dosage forms and undergo release quality control that have not previously been inspected by the authorized body (organization) of at least one Member State;
b) the procedure for bringing into compliance with the requirements of the Union - for medicinal products previously registered in the Member States, in the event of indicating (introducing, changing) a production site (production sites) that have not previously been inspected by the authorized body (organization) of at least one Member State.
34. Preclinical safety studies of medicinal products are conducted in accordance with the requirements of the rules of good laboratory practice of the Union approved by the Commission.
Clinical trials of medicinal products are conducted in accordance with the requirements of the rules of good clinical practice of the Union approved by the Commission.
35. Preclinical safety studies of medicinal products conducted in non-Union member states shall be considered in the course of examination of medicinal products, provided that they are planned, conducted and described in the preclinical study report in accordance with the requirements of good laboratory practice equivalent to the Union requirements (or not lower).
Clinical studies of medicinal products conducted in non-Union member states shall be considered in the course of examination of medicinal products, provided that they are planned, conducted and described in the clinical study report in accordance with the requirements of good clinical practice equivalent to the Union requirements (or not lower), as well as the principles of the World Medical Association Declaration of Helsinki "Ethical Principles for Medical Research Involving Human Subjects".
During the examination of a medicinal product, the authorized body of the reference state has the right to appoint an unscheduled inspection for compliance with the rules of good laboratory practice of the Union in the event of:
identification during the examination of the medicinal product of facts that cast doubt on the reliability of the results obtained during the preclinical studies;
identification of questionable (implausible or contradictory from a medical and biological point of view) research results;
the presence of other circumstances stipulated by the rules for conducting pharmaceutical inspections approved by the Commission.
36. When registering a medicinal product, reports on the clinical trials conducted, included in module 5 of its registration dossier, are considered during the examination if one of the following conditions is met:
clinical trials were conducted in accordance with the legislation of the Member States and on their territory before 1 January 2016 (based on the date of the last visit of the last patient (volunteer)) or continued to be conducted as of 1 January 2016 (with the recruitment of patients (volunteers) into the study completed);
clinical trials were conducted partially or completely in the territories of the countries of the region of the International Conference on Harmonization of Technical Requirements for Registration of Medicinal Products for Human Use (ICH) before January 1, 2016 (according to the date of the last visit of the last patient), on the basis of which the medicinal product was registered in the territories of the countries of the region of the International Conference on Harmonization of Technical Requirements for Registration of Medicinal Products for Human Use (ICH);
clinical trials initiated after January 1, 2016, were conducted in accordance with international treaties and acts constituting the law of the Union, while at least one of the clinical trials was conducted fully or partially (in relation to the data obtained from the subjects of the study) in the territory of the Union.
If the requirements specified in the second to fourth paragraphs of this clause are not met, before filing an application for registration of a medicinal product, the applicant shall conduct clinical trials (at least one trial at the discretion of the applicant and in agreement with the authorized body) in whole or in part on the territory of the Union or, when conducting an examination of the registration dossier, an unscheduled inspection of one of the clinical centers in which the clinical trial was conducted shall be appointed by decision of the authorized body. The provisions of this clause shall not apply to orphan medicinal products.
37. The authorized body of the reference state, on the basis of the documents and information submitted by the applicant and taking into account the assessment of possible risks, makes a decision on the need (or lack of need) to conduct an unscheduled inspection of clinical trials of the medicinal product, including bioequivalence studies, during the registration of the medicinal product for compliance with the requirements of good clinical practice of the Union or to include an inspection of the clinical trial in the plan for inspections in the first 3 years after registration of the medicinal product. In this case, a scheduled inspection is carried out in at least one research center in accordance with the rules for conducting pharmaceutical inspections approved by the Commission.
38. The decision on the need to conduct an unscheduled inspection of a clinical trial for compliance with the requirements of good clinical practice of the Union (or for compliance with the requirements of good laboratory practice of the Union - in relation to applicable points) is made by the authorized body based on a comprehensive assessment of the following factors:
lack of information on approval by an independent ethics committee of the clinical trial;
identification of violations in obtaining informed consent or information provided to research subjects;
(as amended by the decision of the Council of the Eurasian Economic Commission dated 30.01.2020 N 9)
the presence of issues related to the administrative structure of the clinical trial (absence or ambiguity of information);
the presence of significant amendments not reflected in the protocol during the study in accordance with the rules of good clinical practice approved by the Commission;
the absence or insufficiency of information in the protocol and report on the clinical trial describing the determination of indicators of efficacy and (or) safety (regarding the selection, identification, processing of clinical samples, conditions of quantitative determination);
the presence of information on the exclusion of these research subjects from statistical analysis without justification;
identification of facts that cast doubt on the reliability of the information presented in the registration dossier regarding a clinical trial of a medicinal product (unjustified or unclear differences in the efficacy and safety endpoints in the clinical trial protocol and report; inconsistency, inaccuracy or incompleteness of data recording, protocol changes not taken into account in other clinical trial documents, a large number of missing values that could affect the statistical power of the study);
implausibility or inconsistency of clinical data (contradictory results compared with known results of other studies, low frequency of reports of cases of serious adverse reactions and (or) implausible data in favor of the study drug compared with the results of other researchers or other studies, questionable (implausible or contradictory) results from a medical and biological point of view between studies or between study centers);
critical dependence (justification of the efficacy and safety of the drug, as well as the benefit-risk ratio) on the results of only one study or studies on a small sample of subjects; the medicinal product is intended for use by a wide population (e.g. vaccines and other medicinal products that are intended for simultaneous use by large groups of the population);
high probability of ethical issues (participation in the study of vulnerable groups of the population: children, persons with cognitive impairment, patients with diseases that have no alternative therapy, institutionalized patients, etc. in accordance with the requirements of the rules of good clinical practice approved by the Commission);
conducting a clinical trial in a clinical center in a geographical region where the level of requirements for conducting clinical trials is lower than those established within the Union;
availability of information from authorized bodies of states that are not members of the Union regarding problems with compliance with the requirements of good clinical practice by the research center or sponsor;
the presence of circumstances stipulated by the rules for conducting pharmaceutical inspections approved by the Commission.
If there are doubts about the quality of the medicinal product and comparator drugs, including placebo, used in the clinical trial, a decision is made to conduct a pharmaceutical inspection of the production site of this medicinal product for compliance with the requirements of good manufacturing practice of the Union.
(as amended by the {HYPERLINK(«https://docs.eaeunion.org/documents/401/6507/»;»Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36»})
39. The decision on the need to conduct an unscheduled inspection in relation to the results of bioequivalence studies shall be made by the authorized body, taking into account the requirements of paragraphs 37 and 38 of these Rules, based on a comprehensive assessment of the following factors:
a) submission of unreasonably homogeneous (heterogeneous) bioequivalence study data;
b) discrepancy between the number of missing (outlier) values and the expected values for a given active substance or type of measurement;
c) implausibility (inconsistency) of the presented clinical, statistical or analytical data;
d) presence of conflicting results of studies regarding pharmacokinetic parameters or interindividual (intraindividual) variability.
40. An unscheduled inspection of the pharmacovigilance system of the registration certificate holder as part of the registration procedure for a medicinal product shall be carried out in cases stipulated by the rules of good pharmacovigilance practice approved by the Commission.
IV. General principles of examination of medicinal products
41. Examination of medicinal products is carried out to obtain a scientific assessment of the quality, safety and efficacy of medicinal products and the benefit-risk ratio of medicinal products and may include:
a) assessment of documents and information submitted by the applicant in the registration dossier of the medicinal product (assessment of the dossier);
b) conducting laboratory tests for compliance with the requirements of the regulatory document on quality and verification of analytical quality control methods;
c) preparation by the reference state of an expert report on the assessment of the medicinal product;
d) assessment by the state of recognition of the expert report on the assessment, taking into account the documents and information contained in the registration dossier of the medicinal product.
42. The main principles of conducting examination of medicinal products during registration are:
a) independence and legal protection of experts in the exercise of their professional activities;
b) mandatory compliance with the requirements of the legislation of the Member States, international treaties and acts constituting the law of the Union;
c) a scientific approach, completeness, comprehensiveness and objectivity of studies of the objects of examination, ensuring the validity of the results of the examination in accordance with documented accepted criteria of acceptability;
d) competence and high professional level of expert organizations and experts;
e) systematic organization of examination of medicinal products and its methodological support;
f) orientation to the world level of development of science and technology, norms and rules of technical and public safety;
g) publicity of the results of the examination, subject to the preservation of state, official and commercial secrets in accordance with the legislation of the Member States, international treaties and acts constituting the law of the Union.
43. When developing, conducting preclinical (non-clinical) and clinical studies (tests) of a medicinal product, its production, implementing pharmacovigilance and preparing documents provided for the registration procedure, confirmation of registration (re-registration), amendments to the registration dossier or other procedures related to registration, developers, manufacturers and holders of registration certificates of medicinal products and their authorized persons must comply with the legislation of the Member States, international treaties and acts constituting the law of the Union, and also be guided by optimal approaches, the implementation of which will ensure the fulfillment of such requirements and which are set out, among other things, in decisions and recommendations adopted by the Commission. In the event of non-compliance with these recommendations, the applicant must provide a justification for the admissibility of the chosen approach from the point of view of ensuring the quality, efficacy and safety of the medicinal product. The justification provided must be assessed during the examination of medicinal products.
44. The examination of a medicinal product shall not be interrupted for the period of unscheduled pharmaceutical inspections for compliance with the requirements of good practices of the Union (manufacturing, laboratory, clinical, pharmacovigilance), but the final expert assessment report may be drawn up by the authorized body (expert organization) of the reference state only taking into account the results of unscheduled pharmaceutical inspections (if they are carried out). The said inspections must be carried out within a period not exceeding 180 calendar days from the date of the authorized body's decision to initiate the inspection.
45. For medicinal products that require additional safety monitoring in accordance with the requirements of good pharmacovigilance practice of the Union, the general characteristics of the medicinal product for medical use (hereinafter referred to as the SmPC) and the instructions for medical use of the medicinal product (package leaflet) (hereinafter referred to as the instructions for medical use) must include the relevant wording and notes in accordance with the requirements for the instructions for medical use of the medicinal product and the general characteristics of the medicinal product for medical use approved by the Commission.
V. Procedure for registration and examination of medicinal products under the mutual recognition procedure
V.I. Registration and examination of a medicinal product
in the reference state
46. The period for registration and examination of a medicinal product in the reference state must not exceed 140 working days from the date of filing an application for registration of a medicinal product until the date of issue of the registration certificate.
(as amended by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
47. In order to register a medicinal product, the applicant shall submit the following documents and materials to the authorized body (expert organization) of the reference state:
an application in the form established by Appendix No. 2 to these Rules, on paper or in the form of an electronic document signed with an electronic digital signature (electronic signature) in accordance with the legislation of the member state in which such application is submitted (hereinafter referred to as the electronic signature);
documents confirming payment of the fee (duty) for registration and examination of the medicinal product in the case and in the manner established by the legislation of the reference state on paper or in the form of electronic documents signed with an electronic signature;
registration dossier in accordance with Appendices N 1 - 5 to these Rules on electronic media in the form of a set of electronic documents;
samples of medicinal products.
Samples of medicinal products, standard samples of active pharmaceutical ingredients and related impurities, specific reagents and other materials necessary for testing samples of medicinal products specified in paragraph five of this clause shall be submitted in agreement with the expert organization.
Samples of medicinal products, specific reagents and other materials shall be submitted in quantities agreed upon with the expert organization and required to conduct no more than 3-fold analysis in accordance with the requirements of the regulatory document on the quality of medicinal products or other specifications included in the registration dossier, within the time period agreed upon by the authorized body (expert organization), which is not included in the general time period for examination and registration of the medicinal product.
Samples, specific reagents and other materials shall not be submitted if it is impossible to conduct tests in the expert organization due to:
difficult availability of samples of medicinal products, standard samples, specific reagents and other materials (including when they are classified as orphan, high-tech, radiopharmaceutical, narcotic, psychotropic or intended for the treatment of high-cost nosologies due to their high cost);
(as amended by decisions of the Council of the Eurasian Economic Commission of 17.03.2022 N 36, of 22.05.2023 N 60)
impossibility of complying with the conditions for transporting the said samples to the territory of a member state and (or) storing them;
(as amended by decision of the Council of the Eurasian Economic Commission of 17.03.2022 N 36)
lack of special equipment and consumables in the expert organization;
and other reasons by decision of the authorized body (expert organization) in the event of force majeure circumstances or circumstances beyond the control of the parties, including in connection with the specifics of production and quality control of the medicinal product.
In accordance with the requirements of the legislation of a member state, the documents specified in paragraphs two through four of this clause may be submitted using electronic document management without additional submission of relevant documents and information on paper, signed and (or) certified by the electronic signature of the applicant, in the cases provided for by these Rules.
48. In the cases specified in paragraphs eight through eleven of clause 47 of these Rules, laboratory tests are carried out in the quality control laboratory of the manufacturer of the medicinal product in the presence of representatives of the expert organization or in a contract laboratory used by the manufacturer in the presence of representatives of the expert organization.
In cases where it is impossible to conduct laboratory tests in the quality control laboratories of the manufacturer of the medicinal product or contract laboratories used by the manufacturer (under conditions of the threat of occurrence, occurrence and elimination of an emergency situation and (or) in the event of a threat of the spread of diseases that pose a danger to others, diseases and injuries resulting from exposure to unfavorable natural, chemical, biological, radiation factors, in which the presence of a representative of an expert organization is not possible, or in other circumstances (for example, related to the specifics of the production and quality control of a specific medicinal product of the categories specified in paragraphs eight to eleven of clause 47)), in agreement with the authorized body (expert organization), the quality examination is carried out on the basis of the manufacturer's documentation (manufacturer's analysis protocols), including using remote interaction tools, including audio or video communication.
49. Expertise of a medicinal product in the reference state includes:
a) assessment of the completeness, completeness and correctness of execution of documents submitted in the registration dossier;
b) assessment of documents and information submitted by the applicant in the registration dossier of the medicinal product for safety, efficacy and quality;
c) conducting laboratory tests for compliance with the requirements of the regulatory document on the quality and reproducibility of the declared quality control methods carried out in accredited testing laboratories;
d) initiation, if necessary, of a pharmaceutical inspection in the cases established by these Rules;
e) preparation by the reference state of an expert report on the assessment of the medicinal product.
50. The authorized body (expert organization) of the reference state shall, within 10 working days from the date of filing the application for registration, evaluate the completeness, completeness and correctness of the documents submitted in the registration dossier before sending the registration dossier materials for examination. The applicant shall be given no more than 90 working days, not included in the period of registration and examination of the medicinal product, to submit materials missing from the registration dossier, based on the comments of the authorized body (expert organization) of the reference state.
The applicant's response shall be assessed within a period not exceeding 5 working days from the date of receipt of the applicant's response.
51. The authorized body (expert organization) of the reference state rejects the application for registration of a medicinal product in the event of failure to submit the registration dossier materials based on the comments of the authorized body (expert organization) of the reference state and (or) failure to confirm payment of the fee (duty) for registration and examination of the medicinal product in the cases and in the manner established by the legislation of the reference state.
52. When registering and/or examining a medicinal product, the authorized body and/or expert organization of the reference state shall have the right to send the applicant a written and/or electronic request for missing additional information, necessary explanations or clarifications of documents and data submitted in the registration dossier (including proposals to amend the summary of product characteristics, instructions for medical use, layouts of the medicinal product packaging, regulatory documentation on quality or other documents of the registration dossier). After the first request, subsequent requests are allowed only if additional questions arise regarding the information submitted by the applicant in response to the previous request.
The examination, which includes the stages specified in subparagraphs "b" - "d" of paragraph 49 of these Rules, shall be carried out within a period not exceeding 105 working days from the date of assessment of the completeness, completeness and correctness of the execution of the documents submitted in the registration dossier or from the date of receipt by the expert organization of the relevant assignment for the examination.
(paragraph introduced by decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
53. The period for the applicant to submit a response to the request specified in paragraph 52 of these Rules shall not exceed 90 working days from the date of receipt of the request.
(as amended by decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
54. If necessary, based on the relevant justification of the applicant, the period established in paragraph 53 of these Rules may be extended by the authorized body (expert organization) of the reference state. The total period for responding to requests shall not exceed 180 working days.
55. The time for the applicant to submit documents at the request of the authorized body or expert organization during the examination of the medicinal product is not included in the period for the examination and registration of the medicinal product.
56. If the applicant fails to submit the requested documents and information within the specified period, the examination and registration of the medicinal product shall be terminated. The authorized body (expert organization) shall notify the applicant of the decision taken in writing and (or) electronically within 14 working days from the date of this decision.
57. The request of the authorized body (expert organization) of the reference state must be transmitted to the applicant in electronic form via telecommunication channels and shall be considered received after 1 working day from the date of its sending.
(clause 57 as amended by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
58. The decision to initiate an unscheduled pharmaceutical inspection for compliance with good pharmaceutical practices of the Union may be taken by the authorized body (expert organization) of the reference state no later than 70 working days from the date of filing the application for registration.
In the event of a decision to initiate an unscheduled pharmaceutical inspection, the authorized body (expert organization) of the reference state sends the applicant a request on the need to organize an inspection (indicating the reasons for initiation and references to acts of the Union bodies). The response to this request is submitted within the time period specified in paragraphs 53 and 54 of these Rules.
An unscheduled pharmaceutical inspection with the submission of a report on the inspection must be carried out within a period not exceeding the registration period of the medicinal product (within 180 working days from the date of the decision by the relevant authorized body or expert organization to initiate the inspection).
An unscheduled pharmaceutical inspection is organized by the applicant in accordance with the rules for conducting pharmaceutical inspections.
In the event that a pharmaceutical inspection is included in the inspection plan in accordance with paragraph 31 of these Rules, the preparation of the report is completed without taking into account the inspection results.
(clause 58 as amended by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
59. In order to prepare an expert assessment report, the expert organization of the reference state has the right, if necessary, to draw up expert reports on quality aspects, assessment of a new active substance contained in a medicinal product, assessment of the registration dossier for the active substance, preclinical, clinical aspects according to the forms in accordance with Appendices No. 6 - 9, 11 and 22. If the expert organization has carried out the relevant tests, a laboratory test report is drawn up, which must contain information in accordance with Appendix No. 12. The form of the laboratory test report is established by the expert organization in accordance with the legislation of the Member States.
Based on the results of the examination of the registration dossier of a reproduced or hybrid medicinal product, the expert organization of the reference state shall, if necessary, draw up expert reports in the forms provided for in Appendices No. 8, 11 and 22 to these Rules, and, if necessary, draw up a laboratory test protocol containing the information specified in Appendix No. 12 to these Rules. The form of the laboratory test protocol shall be established by the expert organization in accordance with the legislation of the Member States.
(clause 59 as amended by Decision of the Council of the Eurasian Economic Commission dated 22.05.2023 No. 60)
60. Based on the results of the examination of the medicinal product, the expert organization of the reference state shall draw up a final expert report on the assessment of the medicinal product submitted for registration, including an assessment of the explanations received from the applicant, documents and information submitted in response to a request from the expert organization or authorized body, in the form according to Appendix No. 16 to these Rules.
61. Expert reports on quality aspects, preclinical, clinical aspects, and the final expert assessment report shall be prepared in accordance with Appendices No. 13-15 and 23 to these Rules.
62. The expert assessment report must be updated by the expert organization of the reference state when new information appears that is important for assessing the quality, safety, or efficacy of the medicinal product and may affect the benefit-risk ratio of the medicinal product, as part of the procedure for making changes to the registration dossier.
63. If, based on the results of the examination of the medicinal product, the authorized body of the reference state makes a positive decision on registration of the medicinal product, the authorized body of the reference state, within a period not exceeding 10 working days:
a) issues to the applicant a registration certificate for the medicinal product in the form in accordance with Appendix No. 17 to these Rules, the approved SmPC, instructions for medical use, a regulatory document on quality, packaging layouts, an expert assessment report (if necessary, the applicant is issued the approved SmPC, instructions for medical use and packaging layouts of the medicinal product in the official language of the reference state), an agreed risk management plan (if necessary);
b) places information about the medicinal product and the active pharmaceutical substances included in its composition in a single register with the attached approved summary of product characteristics, instructions for medical use, packaging layouts, quality regulatory document, as well as the final expert assessment report compiled in accordance with Appendix No. 16 to these Rules, after the removal of confidential data and data on experts, an agreed risk management plan (if necessary) in accordance with the procedure for the formation and maintenance of a single register.
63.1. A decision based on the results of the examination of the medicinal product shall be made by the authorized body of the reference state within a period not exceeding 10 working days from the date of signing the expert assessment report.
(clause 63.1 was introduced by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
64. The authorized body of the reference state refuses to register a medicinal product based on the results of the examination in the following cases:
a) the ratio of the expected benefit to the possible risks associated with the use of the medicinal product is not favorable;
b) the effectiveness of the medicinal product is not confirmed by the information provided by the applicant;
c) the quality of the medicinal product is not confirmed;
d) the proposed quality control methods and techniques are not reproducible;
e) the applicant has provided false information;
f) the results of the appointed inspection during the registration of the medicinal product do not confirm compliance with the proper pharmaceutical practices of the Union;
g) the applicant has not submitted the documents and information requested by the authorized body (organization) within the specified time period.
(subparagraph "g" introduced by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
65. If the authorized body of the reference state decides to refuse to register a medicinal product, the authorized body (expert organization) of the reference state shall notify the applicant thereof electronically and (or) in writing within 10 working days from the date of such decision.
V.II. Registration and examination of a medicinal product under the mutual recognition procedure in the state (states) of recognition
66. After registration of a medicinal product in the reference state, the applicant may initiate registration in other Member States selected by the applicant as recognition states under the mutual recognition procedure by submitting to the authorized bodies (expert organization) of such Member States:
an application for registration of a medicinal product under the mutual recognition procedure on paper or in the form of an electronic document signed with an electronic signature, in the form according to Appendix No. 2 to these Rules;
(as amended by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No. 36)
documents confirming payment of the fee (duty) for registration and examination of the medicinal product in the case and in the manner established by the legislation of the recognition state, on paper or in the form of electronic documents;
(as amended by the Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No. 36)
module 1 of the registration dossier on an electronic medium in the form of electronic documents (including updated documents related exclusively to the state of recognition). In the cover letter, the applicant is obliged to provide information on all changes made to the registration dossier if they were initiated before the date of filing the application for registration in the state of recognition (indicating the application numbers and attaching copies of the decisions (conclusions) of the authorized body of the reference state).
If there are relevant requirements in the legislation of the member state, the summary of product characteristics, instructions for medical use and packaging layouts of the medicinal product in the official language of the state of recognition are submitted.
The application cannot be submitted to the states of recognition before the date of completion of the procedures for making changes initiated in the reference state (if any). After the registration procedure has been initiated in the recognition states and until it has been completed in the recognition states in which this procedure has been initiated, the applicant may not initiate the procedure for making changes in the reference state, with the exception of urgent changes related to safety.
(paragraph introduced by the Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No. 36)
When submitting urgent changes related to safety in the reference state, the applicant is obliged to notify the authorized body (expert organization) of the recognition state carrying out the recognition procedure of this fact within 24 hours.
In accordance with the requirements of the legislation of a member state, the documents specified in paragraphs two through four of this clause may be submitted using electronic document management without additional submission of relevant documents and information on paper, signed and (or) certified by the electronic signature of the applicant, in cases stipulated by these Rules.
66.1. It is allowed to make changes to the registration dossier of a registered medicinal product in the reference state in accordance with Appendices No. 19 and 20 to these Rules before the date of initiation of the mutual recognition procedure in the state (states) of recognition. In this case, an updated expert report on the results of the changes (if applicable) must be submitted to the state of recognition by the reference state. At the applicant's discretion, it is allowed to initiate the mutual recognition procedure simultaneously in several recognition states.
(paragraph 66.1 was introduced by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
67. The authorized body (expert organization) of the reference state, at the request of the applicant, within a period not exceeding 5 working days from the date of receipt of this request, provides access for the authorized bodies (expert organizations) of the recognition states to the registration dossier of the medicinal product and the expert assessment report through an integrated system using additional documents and information submitted by the applicant in response to requests from the authorized body (expert organization) of the reference state.
68. Registration of a medicinal product in the state of recognition, in the absence of disagreements between the authorized bodies of this Member State and the reference State and in the presence of an opinion on the possibility of recognizing the expert assessment report, is carried out no later than 60 working days from the date of receipt by the expert organization of access to all versions (sequences) of the electronic registration dossier, on the basis of which the reference State prepared the expert assessment report, and to the approved expert assessment report.
69. Examination of a medicinal product under the mutual recognition procedure in the states of recognition is carried out within a period not exceeding 40 working days from the date of receipt of access to the expert assessment report, by:
consideration of the application, documents and information presented in the registration dossier, current (taking into account changes made to the registration dossier, if any) in the reference State at the time of filing the application in the states of recognition;
review of the expert assessment report prepared by the expert organization of the reference state, updated in the reference state at the time of filing the application in the recognition states.
The expert organization of the recognition state notifies the authorized body of the recognition state and the applicant of receiving the specified access in full within 1 working day from the date of its receipt.
The applicant is notified of the start of the examination in electronic form via telecommunication channels. The notification is considered received after 1 working day from the date of its sending (or publication in the applicant's personal account).
(clause 69 as amended by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
70. The authorized body (expert organization) of the state of recognition, within 10 working days from the date of filing the application, rejects the application for registration of a medicinal product under the mutual recognition procedure in the event of non-compliance of the application with the requirements of these Rules and (or) failure to confirm payment of the fee (duty) for registration and examination of the medicinal product in the cases and in the manner stipulated by the legislation of the state of recognition, or makes a decision to begin the examination specified in clause 69 of these Rules.
71. When registering a medicinal product under the mutual recognition procedure, the authorized body (expert organization) of the state of recognition, no later than 30 working days after receiving access to the expert assessment report, if necessary, sends a request to the applicant and to the authorized body (expert organization) of the reference state in the form according to Appendix No. 18 to these Rules.
The request of the authorized body (expert organization) of the state of recognition to the applicant may be submitted to the authorized representative of the applicant in person against signature, sent by registered mail or transmitted electronically via telecommunication channels. If this request is sent by registered mail, it is considered received after 6 calendar days from the date of sending the registered letter. If the request is sent via telecommunication channels, it shall be deemed received after 1 calendar day from the date of its sending.
A request from an authorized body (expert organization) of the state of recognition to an authorized body of the reference state shall be sent using the integrated system.
72. The applicant shall send a response to the request to the authorized body (expert organization) of the state of recognition within a period not exceeding 90 working days. The period for the applicant's response to the request is not included in the total period for the examination and registration of the medicinal product. The authorized body (expert organization) of the state of recognition shall, within 5 working days from the date of receipt of the applicant's response, provide the authorized body (expert organization) of the reference state with access to it through the integrated system.
73. If the applicant fails to submit the documents and information requested by the authorized body (expert organization) of the state of recognition within the established period, the examination and registration of the medicinal product in this state of recognition shall be terminated.
If the authorized body of the reference state fails to submit the documents and information requested by the authorized body (expert organization) of the state of recognition within 100 working days, a conclusion shall be drawn up on the impossibility of recognizing the expert assessment report prepared by the reference state.
The said report shall be sent by the state of recognition for consideration by the Expert Committee.
74. The applicant shall be notified of the decision taken by the authorized body and (or) expert organization (in electronic and (or) paper form) within 10 working days from the date of the decision.
75. The authorized body (expert organization) of the state of recognition, based on the results of the examination of the medicinal product, within 5 working days from the date of completion of the examination specified in paragraph 69 of these Rules, using the integrated system, sends to the authorized body (expert organization) of the reference state a conclusion on the possibility or impossibility of recognizing the expert assessment report prepared by the reference state. The authorized body of the reference state communicates the received conclusion to the applicant in electronic form via telecommunication channels and makes a decision on the possibility or impossibility of recognizing the expert assessment report prepared by the reference state. (paragraph 75 as amended by the Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No. 36)
76. If, based on the results of the examination of the medicinal product, the authorized body of the state of recognition makes a positive decision on registration of the medicinal product, the authorized body of the state of recognition, no later than 5 working days:
a) issues to the applicant a registration certificate of the medicinal product in the form according to Appendix No. 17 to these Rules, as well as the approved summary of product characteristics, instructions for medical use, packaging layouts in the official language of the state of recognition, if there are relevant requirements in the legislation of the state of recognition;
b) approves the regulatory document on quality issued by the reference state;
c) places information about the medicinal product and its active pharmaceutical ingredients in the unified register with the attached approved summary of product characteristics, instructions for medical use, packaging layouts, and an agreed risk management plan (if necessary) in accordance with the procedure for forming and maintaining the unified register.
(as amended by the decision of the Council of the Eurasian Economic Commission of 30.01.2020 N 9)
77. The registration certificate of a medicinal product shall be issued by the authorized body of the state of recognition with the validity period of the registration certificate established by the reference state.
78. Registration of a medicinal product registered in accordance with these Rules in other Member States not specified in the initial application for registration as recognition states, as well as in states that joined the Union after registration of the medicinal product, shall be carried out in accordance with the mutual recognition procedure based on the consideration of the current version of the expert assessment report prepared by the expert organization of the reference state.
79. If it is impossible to recognize the expert assessment report prepared by the expert organization of the reference state, the authorized body (expert organization) of the recognition state shall send to the authorized body (expert organization) of the reference state, other recognition states participating in the registration procedure of the medicinal product, the applicant and the Expert Committee a conclusion on the impossibility of recognizing this expert assessment report, indicating the following reasons:
b) the applicant has not proven the efficacy of the medicinal product;
c) the quality of the medicinal product has not been confirmed;
d) the applicant has submitted inaccurate information;
e) based on the results of the appointed inspection during the registration period of the medicinal product, a non-compliance with the proper pharmaceutical practices of the Union is revealed, which is critical.
80. The Expert Committee, within a period not exceeding 60 calendar days from the date of receipt of the conclusion of the authorized body of the state of recognition on the impossibility of recognizing the expert assessment report prepared by the expert organization of the reference state, shall carry out the procedure for considering disagreements in accordance with the procedure established by the Commission.
81. The authorized body of the state of recognition shall refuse to register a medicinal product if, based on the results of the examination of the medicinal product and after the procedure for settling disagreements in the Expert Committee, it has decided that the data presented in the expert assessment report cannot be recognized as sufficient to confirm the quality and (or) effectiveness, and (or) a favorable benefit-risk ratio of the medicinal product, as well as if the applicant fails to submit within the prescribed period the documents and information requested by the authorized body (expert organization) of the state of recognition.
If, after the dispute resolution procedure has been carried out in the Expert Committee, it has made a unanimous decision that the data presented in the expert assessment report can be recognized as sufficient to confirm the quality and (or) effectiveness and (or) a positive benefit-risk ratio of the medicinal product, the authorized body of the state of recognition, no later than 15 working days from the date of receipt of the decision of the Expert Committee:
makes a decision to recognize the expert assessment report prepared by the expert organization of the reference state;
issues to the applicant a registration certificate for a medicinal product in the form according to Appendix N 17 to these Rules, as well as an approved general characteristic of the medicinal product, instructions for medical use, packaging layouts in the official language of the state of recognition, if there are relevant requirements in the legislation of the state of recognition;
coordinates the regulatory document on quality issued by the reference state;
posts information about the medicinal product and the active pharmaceutical substances included in its composition in a single register with the attached approved general characteristics of the medicinal product, instructions for medical use, packaging layouts, an agreed risk management plan (if necessary) in accordance with the procedure for the formation and maintenance of a single register.
82. In the event of disagreements between authorized bodies regarding the recognition of the expert assessment report and their consideration by the Expert Committee, the authorized body of the state of recognition that made a positive decision on the recognition of the expert assessment report prepared by the expert organization of the reference state issues a registration certificate, approved summary of product characteristics, instructions for medical use, packaging layouts and agrees on a risk management plan (if necessary), a regulatory document on quality until the decision of the Expert Committee. At the request of the applicant, the issuance of a registration certificate by the authorized body of such a recognition state may be suspended until the disagreements between the authorized bodies of other recognition states and the reference state are resolved.
The registration certificate issued in such cases is valid in the territory of this recognition state.
VI. Procedure for registration and examination
under the decentralized procedure in the reference state
and recognition states
83. For the purpose of registering a medicinal product under the decentralized procedure, the applicant shall select the reference state and recognition states.
84. The duration of the decentralized procedure for registration and examination of a medicinal product shall not exceed 140 working days from the date of filing an application for registration of a medicinal product until the date of issuance of a registration certificate in the reference state and shall not exceed 50 working days in the recognition states participating in the decentralized procedure.
(clause 84 as amended by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
85. The registration procedure under the decentralized procedure consists of the following stages, carried out simultaneously:
a) registration and examination of the medicinal product in the reference state;
(subparagraph "a" as amended by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
b) consideration of the expert assessment report prepared by the expert organization of the reference state, in the states of recognition.
(subparagraph "b" as amended by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
86. For the purpose of registering a medicinal product, the applicant shall submit the following documents to the authorized body (expert organization) of the reference state:
an application for registration of a medicinal product on paper or in the form of an electronic document signed with an electronic signature, in the form in accordance with Appendix No. 2 to these Rules;
documents confirming payment of the fee (duty) for registration and examination of the medicinal product in the case and manner established by the legislation of the reference state, on paper or in the form of electronic documents;
registration dossier in accordance with Appendices No. 1 - 5 to these Rules on electronic media in the form of a set of electronic documents;
Samples of medicinal products, standard samples of active pharmaceutical substances and related impurities, specific reagents and other materials necessary for testing the samples specified in paragraph five of this clause shall be submitted in agreement with the expert organization.
Samples, specific reagents and other materials shall be submitted in quantities agreed upon with the expert organization, necessary for conducting no more than a 3-fold analysis in accordance with the requirements of the regulatory document on the quality of medicinal products within the time period agreed upon by the authorized body (expert organization) and not included in the general time period for examination and registration of the medicinal product.
In accordance with the requirements of the legislation of a member state, the documents specified in paragraphs 2 - 4 of this clause may be provided in the form of electronic document management without additional submission of relevant documents and information on paper, signed and (or) certified by the electronic signature of the applicant, in the cases provided for by these Rules.
87. In the case specified in paragraph eight of clause 86 of these Rules, laboratory tests are carried out in the quality control laboratory of the manufacturer of the medicinal product or in a contract laboratory used by the manufacturer, in the presence of representatives of the expert organization.
In the event that it is impossible to conduct laboratory tests in the manufacturer's quality control laboratories or contract laboratories used by the manufacturer (under conditions of a threat of occurrence, occurrence and elimination of an emergency situation and (or) in the event of a threat of the spread of diseases posing a danger to others, diseases and injuries resulting from exposure to unfavorable natural, chemical, biological, radiation factors, in which the presence of a representative of an expert organization is not possible, or in other circumstances (for example, related to the specifics of the production and quality control of a specific medicinal product related to the categories specified in paragraphs eight to twelve of clause 86 of these Rules)), in agreement with the authorized body (expert organization) of the reference state, the quality examination is carried out on the basis of the manufacturer's documentation (manufacturer's analysis protocols), including using remote interaction tools, including audio or video communication. (paragraph introduced by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
88. Within 14 working days from the date of submission of documents to the authorized body (expert organization) of the reference state, the applicant shall submit to the authorized bodies (expert organizations) of the states of recognition:
an application on paper or in the form of an electronic document signed with an electronic signature, in the form in accordance with Appendix No. 2 to these Rules;
module 1 of the registration dossier on electronic media in the form of a set of electronic documents;
documents confirming payment of the fee (duty) for registration and examination in the case and manner established in accordance with the legislation of the state of recognition in the form of electronic documents.
If there are relevant requirements in the legislation of a member state, the summary of product characteristics, instructions for medical use and layouts of the packaging of the medicinal product shall be submitted in the official language of the state of recognition.
In accordance with the requirements of the legislation of a member state, the submission of the documents specified in paragraphs two through four of this clause may be carried out using electronic document management without additional submission of relevant documents and information on paper, signed and (or) certified by the electronic signature of the applicant, in the cases stipulated by these Rules.
89. Expertise of a medicinal product in the reference state under the decentralized registration procedure includes:
a) assessment of the completeness, completeness and correctness of the submitted documents of the registration dossier;
b) assessment of the documents and data submitted by the applicant in the registration dossier of the medicinal product for safety, efficacy and quality;
e) preparation of an expert report on the assessment of the medicinal product by the reference state.
90. Expertise of a medicinal product in the states of recognition under the decentralized registration procedure is carried out by reviewing:
a) the application, documents and data of the registration dossier;
b) the expert assessment report prepared by the reference state.
91. The authorized body (expert organization) of the reference state, within 10 working days from the date of filing the application for registration, shall assess the completeness, completeness and correctness of the submitted documents of the registration dossier before sending the materials of the registration dossier for examination. The applicant shall be given no more than 90 working days, not included in the period of registration and examination of the medicinal product, to submit missing materials of the registration dossier at the request of the authorized body (expert organization) of the reference state. (as amended by the Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No. 36)
The request of the authorized body (expert organization) of the reference state must be transmitted to the applicant in electronic form via telecommunication channels and is considered received after 1 calendar day from the date of its sending.
The assessment of the applicant's response is carried out within a period not exceeding 5 working days from the date of receipt of the applicant's response.
The authorized body (expert organization) of the reference state, no later than 14 working days from the date of completion of the assessment of the completeness and completeness of the submitted materials of the registration dossier, provides access to the registration dossier of the medicinal product to the authorized bodies (expert organizations) of the recognition states participating in the procedure for decentralized registration of the medicinal product through the use of an integrated system or notifies of the rejection of the application in the manner established by paragraph 92 of these Rules.
The examination, which includes the stages specified in subparagraphs "b" - "d" of paragraph 89 of these Rules, shall be carried out within a period not exceeding 105 working days from the date of assessment of the completeness, completeness and correctness of execution of the documents submitted in the registration dossier, or from the date of receipt by the expert organization of the relevant assignment for the examination.
92. The authorized body (expert organization) of the reference state rejects the application for registration of a medicinal product in the event of failure to submit within the specified time period the documents and materials of the registration dossier based on the comments of the authorized body (expert organization) of the reference state and (or) failure to confirm payment of the fee (duty) for registration and examination of the medicinal product in the cases and in the manner established by the legislation of the reference state, and informs the applicant and the authorized bodies (expert organizations) of the states of recognition through the integrated system within no more than 5 working days from the date of the decision.
93. When registering and examining a medicinal product, the authorized body (expert organization) of the reference state has the right to send the applicant a written and/or electronic request for the submission of missing additional information, necessary explanations or clarifications concerning the submitted documents and data of the registration dossier (including proposals to amend the summary of product characteristics, instructions for medical use, layouts of the medicinal product packaging, regulatory document on quality or other documents of the registration dossier). (as amended by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
94. The authorized body (expert organization) of the reference state, within 60 working days from the date of commencement of the examination, shall send to the authorized bodies (expert organizations) of the recognition states copies of reports with the wording of comments in the form in accordance with Appendices No. 6 - 8 to these Rules or a preliminary assessment report in the form in accordance with Appendix No. 11 to these Rules or copies of requests to the applicant.
The examination in the reference state shall be suspended until the day of receipt from all recognition states participating in the procedure of additional comments or information on agreement with the preliminary report or request of the reference state.
In the event of an examination of the registration dossier of a reproduced or hybrid medicinal product, the authorized body (expert organization) of the reference state, within 60 working days from the date of commencement of the examination, shall send to the authorized bodies (expert organizations) of the states of recognition copies of reports with the wording of comments and requests to the applicant in the form in accordance with Appendices No. 8 and 22 to these Rules or a preliminary assessment report in the form in accordance with Appendix No. 11 to these Rules, or copies of requests to the applicant.
If there are any additional comments addressed to the applicant, the authorized body (expert organization) of the state of recognition, no later than 30 working days from the date of receipt of the preliminary assessment report of the reference state, sends requests to the authorized body (expert organization) of the reference state, which, within 20 working days from the date of receipt of the last request from the state of recognition or information on consent with the preliminary report of the reference state, forms a single request and sends it to the applicant in accordance with paragraph 93 of these Rules.
From the date of sending comments to the applicant, further examination is suspended. After the first request, subsequent requests are allowed only if additional questions arise regarding the data provided by the applicant in response to the previous request.
95. The period for the applicant to submit a response to the specified request shall not exceed 90 working days. The procedures for sending requests and submitting responses shall be established by the requirements of the legislation of the member states.
If necessary, based on the relevant application of the applicant, the deadline for responding to a request may be extended by the authorized body of the reference state. The general deadline for responding to requests shall not exceed 180 working days.
96. The total period for the applicant to submit responses to requests from the authorized body (expert organization) during the registration procedure shall not exceed 180 working days.
The time for the applicant to submit documents at the request of the authorized body (expert organization) during the examination of a medicinal product shall not be included in the time frame for the examination and registration of the medicinal product.
97. After the applicant submits responses to requests to the authorized body (expert organization) of the reference state, the examination shall be resumed.
98. If the applicant fails to submit the documents and materials requested by the authorized body (expert organization) within the specified time frame, the examination and registration of the medicinal product shall be terminated. The authorized body (expert organization) shall notify the applicant and authorized bodies (expert organizations) of the decision taken within 14 working days from the date of adoption of such decision in written and/or electronic form.
99. The decision to initiate an unscheduled pharmaceutical inspection for compliance with good pharmaceutical practices of the Union may be taken by the authorized body (expert organization) of the reference state no later than 70 working days from the date of filing the application for registration.
In the event of a decision to initiate an unscheduled pharmaceutical inspection, the authorized body (expert organization) of the reference state sends the applicant a request on the need to organize an inspection with a detailed indication of the reasons for the initiation and references to the acts of the Union bodies.
An unscheduled pharmaceutical inspection with the submission of a report on the inspection carried out must be carried out within a period not exceeding the registration period of the medicinal product (within 180 working days from the date of the decision by the relevant authorized body to initiate the inspection).
In the event that pharmaceutical inspection is included in the inspection plan in accordance with paragraph 31 of these Rules, the preparation of the report shall be completed without taking into account the inspection results.
(paragraph 99 as amended by the Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
100. Interaction between authorized bodies (expert organizations) when sending requests to the applicant shall be carried out electronically in the form in accordance with Appendix N 18 to these Rules using the tools of the integrated system.
101. In the absence of additional comments from any recognition state regarding the examination of a medicinal product (submission of comments, results of consideration of the preliminary assessment report), this recognition state shall provide the reference state with information that it agrees with the conclusion (including comments, if applicable) contained in the preliminary assessment report in accordance with paragraph 94 of these Rules.
(paragraph 101 as amended by the Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No. 36)
102. Written consultations between the authorized bodies (expert organizations) of the reference state and the states of recognition, if necessary, shall be carried out electronically using the tools of the integrated system.
103. In order to prepare the final expert assessment report, the expert organization of the reference state has the right, if necessary, to draw up expert reports on quality aspects, assessment of a new active substance contained in a medicinal product, assessment of the registration dossier for the active substance, preclinical, clinical aspects according to the forms provided for in Appendices No. 6 - 9, 11 and 22 to these Rules. If the expert organization has carried out the relevant tests, a laboratory test report shall be drawn up, which must contain the mandatory information provided for in Appendix No. 12 to these Rules. The form of the laboratory test protocol is established by the expert organization in accordance with the legislation of the Member States. (as amended by the decision of the Council of the Eurasian Economic Commission of 22.05.2023 N 60)
Based on the results of the examination of the registration dossier of a reproduced or hybrid medicinal product, the expert organization of the reference state, if necessary, draws up expert reports in the forms provided for in Appendices No. 8, 10 and 22 to these Rules, and, if necessary, draws up a laboratory test protocol containing the information provided for in Appendix No. 12 to these Rules. The form of the laboratory test protocol is established by the expert organization in accordance with the legislation of the Member States.
(as amended by the decision of the Council of the Eurasian Economic Commission dated 22.05.2023 No. 60)
Expert reports on quality aspects, preclinical, clinical aspects, the final expert report on the assessment are drawn up in accordance with the instructions provided in Appendices No. 13 - 15 and 23 to these Rules.
The final expert report on the assessment of the reference state is drawn up in the form according to Appendix No. 16 to these Rules.
104. No later than 90 working days from the date of filing an application for registration, the authorized body (expert organization) of the reference state may send to the recognition states and the applicant a draft final expert assessment report in the form in accordance with Appendix No. 16 to these Rules together with the applicant's responses to inquiries, a draft general characteristics of the medicinal product, a draft instruction for medical use (package insert), a draft packaging layout, a draft regulatory document on quality, and, if necessary, a draft risk management plan.
If the expert organization of the reference state has prepared a negative draft final expert assessment report and a decision has been made to refuse registration in accordance with paragraph 114 of these Rules, the examination and registration of the medicinal product shall be terminated. The authorized body (expert organization) shall notify the applicant of the decision taken within 14 working days from the date of such decision in written and (or) electronic form with the specified final expert assessment report attached.
If the expert organization of the reference state has prepared a positive draft of the final expert assessment report, it shall be reviewed by the authorized bodies (expert organizations) of the recognition states.
105. In the absence of comments from the authorized bodies (expert organizations) of the recognition states or after their withdrawal in accordance with paragraph 106 of these Rules, the authorized body (expert organization) of the reference state and the recognition states shall complete the procedure for examining the medicinal product within 10 working days (the 117th working day from the date of filing the application for registration).
106. If there are comments from the authorized bodies (expert organizations) of the states of recognition on the draft final expert assessment report, the draft summary of product characteristics, the draft instructions for medical use, the draft packaging layouts or the draft regulatory document on quality, the draft risk management plan (if necessary), the authorized bodies (expert organizations) of the states of recognition, if necessary, consult with the authorized body (expert organization) of the reference state or states of recognition in electronic form within 10 working days in the form in accordance with Appendix No. 18 to these Rules (the 110th working day from the date of filing the application for registration).
(as amended by Decisions of the Council of the Eurasian Economic Commission of 30.01.2020 N 9, of 17.03.2022 N 36)
107. In the event of any unresolved disagreements within the framework of mutual consultations, the authorized body (expert organization) of the state of recognition, within a period not exceeding 10 working days from the date of receipt of the final expert report on the assessment of the reference state, taking into account the conditions of paragraph 106 of these Rules, using the means of the integrated system, shall send a conclusion on the impossibility of recognizing the expert report on the assessment prepared by the expert organization of the reference state, with a justification for the reasons for the negative decision to the authorized body (expert organization) of the reference state and the states of recognition, as well as to the Expert Committee, including on paper.
108. The Expert Committee, within a period not exceeding 60 calendar days from the date of sending by the states of recognition of the conclusion on the impossibility of recognizing the positive expert report on the assessment prepared by the expert organization of the reference state, shall carry out the procedure for settling disagreements in accordance with the procedure established by the Commission. If the disagreements between the authorized bodies of the reference state and the recognition states regarding the recognition of the expert assessment report are resolved, they shall proceed to the completion of the examination procedure and the procedure for issuing final documents in accordance with paragraphs 105 and 109-113 of these Rules.
If the disagreements between the authorized bodies of the reference state and the recognition states regarding the recognition of the expert assessment report are not resolved, the authorized bodies of the reference state and the recognition states that have made a positive decision to recognize the expert assessment report shall proceed to the completion of the examination procedure and the procedure for issuing final documents in accordance with paragraphs 105 and 109-113 of these Rules. At the request of the applicant, the issuance of a registration certificate by the authorized bodies of such member states may be suspended until the disagreements between the authorized bodies of other recognition states and the reference state are resolved.
109. The authorized bodies (expert organizations) of the reference state and recognition states that have made a positive decision based on the results of the examination on the possibility of registering a medicinal product in accordance with paragraphs 105 and 108 of these Rules, shall proceed to the procedure for issuing final documents within a period of no more than 20 working days. (paragraph 109 as amended by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
110. No later than 20 working days from the date of the authorized body's positive decision on registration:
a) the authorized body of the reference state issues to the applicant a registration certificate for the medicinal product in the form in accordance with Appendix No. 17 to these Rules, the approved SmPC, instructions for medical use, quality regulatory document, packaging layouts, expert assessment report (if necessary, the applicant is issued the approved SmPC, instructions for medical use and packaging layouts of the medicinal product in the official language of the reference state), and, if necessary, an agreed risk management plan;
b) the authorized bodies of the states of recognition issue to the applicant registration certificates of the medicinal product in the form in accordance with Appendix No. 17 to these Rules, approved SmPC, instructions for medical use, packaging layouts in the official languages of the states of recognition (if there are relevant requirements in the legislation of the member states), and, if necessary, an agreed risk management plan.
111. The authorized bodies of the reference state and the states of recognition shall post information on the registration of the medicinal product and the active pharmaceutical substances included in it in a single register with the attached approved summary of product characteristics, instructions for medical use, packaging layouts, quality regulatory document, as well as the final expert assessment report compiled in accordance with Appendix No. 16 to these Rules, after the removal of confidential data and data on experts, a summary of the agreed risk management plan (if necessary) in accordance with the procedure for the formation and maintenance of a single register.
112. The registration certificate of the medicinal product shall be issued by the authorized body of the state of recognition with the validity period of the registration certificate established by the authorized body of the reference state.
113. The expert assessment report shall be updated by the reference state when new information emerges that is important for assessing the quality, safety or efficacy of the medicinal product as part of the procedure for amending the registration dossier.
114. The authorized body of the reference state shall refuse registration under the decentralized procedure in the following cases:
b) the efficacy of the medicinal product is not confirmed by the data submitted by the applicant;
e) the applicant has submitted inaccurate information;
f) the results of the appointed inspection during the registration of the medicinal product do not confirm compliance with good pharmaceutical practices of the Union;
g) the applicant has not submitted a response to the request sent in accordance with paragraph 94 of these Rules within the prescribed time limit.
115. The authorized body of the recognition state shall not recognize the expert assessment report prepared by the expert organization of the reference state, and thereby refuse registration under the decentralized procedure if, based on the results of the examination of the registration dossier of the medicinal product and after the dispute resolution procedure in the Expert Committee, it has decided that the data presented in the expert assessment report cannot be recognized as sufficient to confirm the quality and (or) effectiveness and (or) favorable benefit-risk ratio of the medicinal product.
VII. Establishment of Post-Registration Measures
(as amended by Decision of the Council of the Eurasian Economic Commission
of March 17, 2022, No. 36)
VII.I. Registration of a Medicinal Product with the Establishment of
Additional Requirements
116. The authorized body (expert organization) of the reference state may establish one or more of the following additional requirements for a medicinal product during its registration and related procedures:
inclusion of certain measures in the risk management system to ensure the safe use of the medicinal product;
conducting post-registration safety studies of the medicinal product;
establishing additional requirements for the registration of the medicinal product and the reporting of suspected adverse reactions;
conducting post-registration studies of the medicinal product's efficacy, and, if necessary, studies of various aspects of the medicinal product's efficacy that cannot be studied prior to marketing;
other conditions or restrictions for the safe and effective use of the medicinal product in accordance with the requirements of the Good Pharmacovigilance Practice Rules of the Eurasian Economic Union.
The established conditions and restrictions, as well as the deadlines for their fulfillment, are specified in the registration certificate, the unified register, the summary of product characteristics, and the instructions for medical use.
117. The authorized body (expert organization) of the reference state may revoke the registration certificate of a medicinal product if the registration certificate holder fails to comply with additional requirements established by the authorized body (expert organization) of the reference state with respect to the medicinal product during its registration and the implementation of registration-related procedures in accordance with paragraph 116 of these Rules.
118. A condition for registration and confirmation of registration (re-registration) of a medicinal product by the authorized body (expert organization) may be the obligation for the registration certificate holder to conduct:
a) post-registration safety studies of the medicinal product if there are concerns regarding the risks associated with the use of the medicinal product. If the risks relate to more than one medicinal product, the authorized bodies of Member States shall facilitate joint post-registration safety studies by registration certificate holders of such medicinal products;
b) post-registration efficacy studies of the medicinal product if the understanding of the disease or clinical methodology indicate that previous efficacy assessments require significant revision.
119. The Marketing Authorization Holder has the right to submit a written explanation on paper or as an electronic document signed with an electronic signature in response to the introduction of the obligation stipulated by paragraph 118 of these Rules, within 90 business days from the date of receipt of the corresponding notification from the authorized body (expert organization) regarding the introduction of the obligation.
120. Based on the written explanation submitted by the Marketing Authorization Holder for the medicinal product in accordance with paragraph 119 of these Rules, the authorized body (expert organization) must waive or confirm the obligation to conduct the studies specified in paragraph 118 of these Rules within 20 business days. If the obligation is confirmed, the terms of registration of the medicinal product (by including the relevant provisions) and the risk management systems must be amended.
VII.II. Registration of the medicinal product
in exceptional cases
120.1. In exceptional cases, after consultation with the applicant, registration may be granted subject to certain conditions, in particular those concerning the safety of the medicinal product, notification of authorized bodies of Member States of each incident related to its use, and the measures taken.
Registration may be granted if the applicant can demonstrate that they are unable to provide comprehensive data on the efficacy and safety of the medicinal product under normal conditions of use due to objective, verifiable reasons, which must correspond to one of the grounds set out in Section 11 of Appendix No. 1 to these Rules.
The continued presence of a medicinal product subject to the procedures described in this paragraph on the Union market shall be subject to a reassessment of such conditions, conducted annually by the authorized body (expert organization) of the reference Member State, with the preparation of an expert report on the assessment of the medicinal product.
The procedural details for the application of this paragraph are set out in Appendix No. 25 to these Rules.
VII.III. Conditional Registration of a Medicinal Product
120.2. If the need to address unmet medical needs for medicinal products intended for the treatment, prevention, or diagnosis of serious (severe) disabling or life-threatening diseases is justified, registration may be granted prior to the submission of comprehensive clinical data, as required by Section 5 of Appendix No. 1 to these Rules, at the time of filing the registration application, provided that the benefit of earlier market availability of the medicinal product in question outweighs the risk associated with the lack of comprehensive data. In cases of urgent need for such medicinal products, their registration may be granted without the provision of comprehensive preclinical or biopharmaceutical data.
120.3. For the purposes of this subsection, "unmet medical need" means a condition for which there is no approved, authorized, and recognized effective diagnostic, prophylactic, or therapeutic method in the Union, or for which the use of a medicinal product submitted for conditional registration would offer a significant advantage over a diagnostic, prophylactic, or therapeutic method already approved by competent authorities.
120.4. Conditional registration may only be granted if the benefit-risk ratio of the medicinal product is positive and if the applicant is likely to be able to provide comprehensive missing data on the safety, efficacy, and quality of the medicinal product after the conditional registration procedure.
120.5. Conditional registration must be accompanied by the fulfillment by the marketing authorization holder of special conditions. These special conditions and the deadline for their fulfillment as conditions of registration shall be established by the competent authority of the Member State and shall be subject to annual assessment by this competent authority.
120.6. Under the special conditions specified in paragraph 120.5, the holder of a marketing authorization issued in accordance with this section must be required to complete ongoing studies or conduct new studies to confirm a positive benefit-risk balance.
120.7. The SmPC and instructions for medical use (package insert) must clearly state that the medicinal product has been registered subject to the special conditions specified in paragraph 120.5 of these Rules.
120.8. Registration issued in accordance with this section is valid for one year and requires confirmation of registration (re-registration) with an annual reassessment of the benefit-risk balance.
120.9. If the special conditions specified in paragraph 120.5 of these Rules are met, the authorized body of the Member State may, upon application by the marketing authorization holder and after receiving a positive opinion from the expert organization, issue a marketing authorization valid for 5 years and subject to renewal in accordance with Section VIII of these Rules.
120.10. A description of the procedures, criteria, and requirements for registration in accordance with this Section is provided in Appendix No. 26 to these Rules.
VII.IV. Accelerated Expertise of Medicinal Products
120.11. 120.11. Accelerated expert evaluation of medicinal products applies to:
orphan medicinal products;
medicinal products intended exclusively for use by minors;
Medicinal products of particular importance to public health, in particular, in the absence of effective methods of providing medical care in Member States, as determined by the Expert Committee on Medicinal Products based on an application from the authorized body of the Member State in which the applicant has submitted an application regarding the particular importance of the medicinal product prior to the submission of the registration application.
The registration and expert review period for a medicinal product in the reference state must not exceed 100 working days from the date of submission of the application for registration of the medicinal product to the date of issuance of the registration certificate.
The procedure for reviewing an application for accelerated expert review of a medicinal product is provided in Appendix No. 27 to these Rules.
VII.V. General Provisions
120.12. The authorized body (expert organization) of the reference state shall act in accordance with the provisions of Section X of these Rules in the event of the marketing authorization holder's failure to comply with additional requirements or obligations established by the authorized body (expert organization) of the reference state with respect to the medicinal product in question during its registration and the implementation of registration-related procedures, in accordance with the provisions of this section.
VIII. Confirmation of Registration (Re-registration)
of a Medicinal Product
121. The date of confirmation of registration (re-registration) of a medicinal product for all Member States in which the medicinal product is registered is determined by the date of registration of the medicinal product in the reference Member State under the mutual recognition procedure or decentralized procedure.
For medicinal products that are not recognized as orphan products in the territory of any Member State in accordance with its legislation, the date of confirmation of registration (re-registration) is determined by the date of registration of the medicinal product in that Member State under the mutual recognition procedure.
122. Confirmation of registration (re-registration) is carried out based on a reassessment of the benefit-risk ratio, conducted by the authorized body (expert organization) of the reference Member State, with the preparation of an expert report on the assessment of the medicinal product.
The assessment of a medicinal product during registration confirmation (re-registration) in the Member States is carried out by:
reviewing the application, documents, and data from the registration dossier;
reviewing the expert assessment report prepared by the reference Member State.
During the registration confirmation (re-registration) procedure for a medicinal product, its circulation within the Union is permitted.
123. The applicant shall submit applications for registration confirmation (re-registration) to all Member States in which the medicinal product is registered.
The applicant has the right to withdraw their application at any time before the completion of the registration confirmation (re-registration) procedure for a medicinal product by notifying in writing the authorized body of the Member State in which the application is being considered.
(paragraph introduced by Decision No. 14 of the Council of the Eurasian Economic Commission dated 05.03.2021)
If an application is withdrawn, the authorized body of the Member State in which the application is being considered shall cease its consideration on the merits and return the original documents and/or information submitted with the application to the applicant. (paragraph introduced by Decision of the Council of the Eurasian Economic Commission dated 05.03.2021 No. 14)
124. If the holder of a registration certificate for a medicinal product fails to submit an application for confirmation of registration (re-registration) before the expiration of the registration certificate, the registration certificate for the medicinal product shall be deemed invalid.
125. The procedure for confirmation of registration (re-registration) shall not exceed 80 working days from the date of submission of the application for confirmation of registration (re-registration) in the reference state and 50 working days in each of the recognition states participating in the procedure.
(paragraph 125 as amended by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No. 36)
126. An application for confirmation of registration (re-registration) of a medicinal product shall be submitted no earlier than 140 working days before the expiration of the registration certificate for the medicinal product in the reference state, but no later than the expiration date of the registration certificate.
(as amended by Decision of the Council of the Eurasian Economic Commission of 17.03.2022 No. 36)
127. In order to confirm the registration (re-registration) of a medicinal product, the applicant shall submit the following documents to the authorized body (expert organization) of the reference state:
a) an application for registration (re-registration) of a medicinal product on paper or as an electronic document signed with an electronic signature, in the form in accordance with Appendix No. 2 to these Rules;
(subparagraph "a" as amended by Decision of the Council of the Eurasian Economic Commission of 17.03.2022 No. 36)
b) documents confirming payment of the fee (duty) for confirmation of registration (re-registration) and examination in the case and according to the procedure established in accordance with the legislation of the reference state, on paper or in the form of an electronic document;
(as amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated 17.03.2022)
c) Modules 1 and 2 of the registration dossier, prepared in accordance with Appendices No. 1–5 to these Rules, on electronic media; If an application is submitted to confirm the registration of a medicinal product based on documents from a registration dossier brought into compliance with the requirements of the Union and subject to the post-registration period obligations stipulated by Section VII of these Rules, at the request of the authorized body (expert organization), the applicant may additionally submit documents from Modules 1 and 3, as well as Modules 4 and 5 (if necessary), that were not previously submitted in the registration dossier;
(as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated 20.10.2023)
d) In accordance with the requirements of the legislation of a Member State, the submission of the documents specified in subparagraphs "a" - "c" of this paragraph may be carried out using electronic document management without the additional submission of the relevant documents and information on paper, signed and/or certified by the electronic signature of the applicant, in cases stipulated by these Rules.
(subparagraph "d" introduced by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No. 36)
128. The authorized body (expert organization) of the reference state, within a period not exceeding 5 working days from the date of submission by the applicant of the documents specified in paragraph 127 of these Rules, shall provide the authorized bodies (expert organizations) of the recognition states with access to the registration dossier of the medicinal product using the tools of the integrated system.
The authorized bodies (expert organizations) of the recognition states shall receive the registration dossier of the medicinal product using the tools of the integrated system.
129. No later than 14 working days from the date of submission of the application for confirmation of registration (re-registration) in the reference state, the applicant shall submit the following documents to the authorized body (expert organization) of each recognition state:
a) an application on paper or in the form of an electronic document signed with an electronic signature, in the established form in accordance with Appendix No. 2 to these Rules;
(subparagraph "a" as amended by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No. 36)
b) documents confirming payment of the fee (duty) for confirmation of registration (re-registration) and examination in the case and according to the procedure established in accordance with the legislation of the recognition states, on paper or in the form of an electronic document;
c) Module 1 of the registration dossier, on electronic media in the form of electronic documents;
d) if the legislation of a Member State provides for the relevant requirements, the summary of product characteristics, instructions for medical use, and packaging layouts of the medicinal product shall also be submitted in the official language of the State of recognition;
e) in accordance with the requirements of the legislation of a Member State, the submission of the documents specified in subparagraphs "a" - "d" of this paragraph may be carried out using electronic document management without the additional submission of relevant documents and information on paper, signed and/or certified by the electronic signature of the applicant, in cases stipulated by these Rules.
(Subparagraph "d" introduced by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No. 36)
130. The authorized body (expert organization) of the reference state, within 10 business days from the date of filing an application for confirmation of registration (re-registration), shall assess the completeness, completeness, and correctness of the submitted registration dossier documents before sending the registration dossier materials for expert review. The applicant shall be given no more than 90 business days, not included in the period for confirmation of registration (re-registration) and expert review of the medicinal product, to submit missing registration dossier materials based on the comments of the authorized body (expert organization) of the reference state.
The request from the authorized body (expert organization) to the applicant must be transmitted electronically via telecommunications channels and is considered received after 1 day from the date of its submission.
(paragraph introduced by Decision No. 36 of the Council of the Eurasian Economic Commission dated March 17, 2022)
The applicant's response will be assessed within 5 business days from the date of receipt of the applicant's response (paragraph introduced by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
131. The authorized body (expert organization) of the reference state shall reject an application for confirmation of registration (re-registration) of a medicinal product in cases of failure to submit missing materials from the registration dossier in response to previously submitted comments within the prescribed timeframe and (or) failure to confirm payment of the fee (duty) for confirmation of registration (re-registration) and examination of the medicinal product in the cases and in the manner established by the legislation of the reference state, as well as in connection with a violation of the deadline for filing an application for confirmation of registration (re-registration) specified in paragraph 126 of these Rules, and shall notify the authorized bodies (expert organizations) of the states of recognition and the applicant thereof in writing and (or) electronically.
132. Within 30 working days of the commencement of the subject matter examination or receipt of the relevant assignment to conduct the examination, the authorized body (expert organization) of the reference State shall prepare a preliminary expert report containing comments in the form specified in Appendix No. 11 to these Rules, or a draft request to the applicant, and shall send it using the integrated system to the authorized bodies (expert organizations) of the recognition States.
The examination in the reference State shall be suspended until the day additional comments or information on agreement with the preliminary report or request of the reference State are received from all recognition States participating in the procedure. (paragraph 132 as amended by Decision N 36 of the Council of the Eurasian Economic Commission dated 17.03.2022)
133. In the event of disagreement with the conclusions presented in the preliminary expert assessment report of the reference state regarding the benefit-risk ratio of the medicinal product, or in the presence of a request from the authorized bodies (expert organizations) of the states of recognition to amend the summary of product characteristics, instructions for medical use, packaging layouts of the medicinal product or other documents of the registration dossier, the authorized body (expert organization) of the state of recognition, no later than 20 working days from the date of receipt by the authorized body (expert organization) of the reference state of the preliminary expert assessment report, using the means of the integrated system, sends a corresponding substantiated request to the authorized body (expert organization) of the reference state.
(as amended by Decision N 36 of the Council of the Eurasian Economic Commission dated 17.03.2022)
134. During the consideration by the authorized bodies (expert organizations) of the recognition states of the preliminary expert assessment report prepared by the expert organization of the reference state, the consideration by the authorized bodies (expert organizations) of the reference state of requests from the authorized bodies (expert organizations) of the recognition states and the consideration by the authorized bodies (expert organizations) of the recognition states of the final expert assessment report prepared by the expert organization of the reference state, consultations may be carried out between the authorized bodies (expert organizations) of the member states participating in the procedure, using the means of the integrated system within the time period specified in paragraph 133 of these Rules, in the form in accordance with Appendix No. 18 to these Rules in order to agree on the final expert assessment report to be prepared by the expert organization of the reference state based on the results of the procedure.
(clause 134 as amended by the decision of the Council of the Eurasian Economic Commission of 17.03.2022 N 36)
135. During the registration confirmation (re-registration) and expert examination of a medicinal product, the authorized body (expert organization) of the reference state may, no later than 10 business days from the date of receipt of additional comments from the authorized bodies (expert organizations) of the states of recognition or information on agreement with the preliminary expert report prepared by the reference state, send the applicant, in written and/or electronic form, a consolidated request for missing additional information, necessary clarifications, or clarifications regarding the submitted documents and data in the registration dossier (including proposals for amendments to the general characteristics of the medicinal product, instructions for medical use, medicinal product packaging layouts, quality regulatory documents, or other documents in the registration dossier).
(as amended by Decision of the Council of the Eurasian Economic Commission dated March 17, 2022, No. 36)
The applicant's deadline for submitting a response to this request shall not exceed 90 business days. The time required for the applicant to submit documents requested by the authorized body (expert organization) of the reference state during the confirmation (re-registration) and expert examination of a medicinal product is not included in the timeframe for the confirmation (re-registration) and expert examination of the medicinal product.
(as amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated March 17, 2022)
The expert organization of the reference state shall, as part of the expert examination of the medicinal product, review the applicant's response and prepare a final expert report in accordance with Appendix No. 16 to these Rules within no more than 20 business days.
If the applicant fails to submit the requested documents and data within the specified timeframe, the expert examination and confirmation of registration (re-registration) of the medicinal product shall be terminated. The authorized body (expert organization) of the reference state shall notify the authorized bodies (expert organizations) of the recognizing states and the applicant of the decision taken within 14 working days from the date of such decision in written and/or electronic form.
136. Based on the results of the medicinal product examination, the authorized body (expert organization) of the reference state shall prepare and approve a final expert assessment report in accordance with the form set out in Appendix No. 16 to these Rules. This report shall be sent, using the integrated system, to the authorized bodies (expert organizations) of all recognizing states participating in the procedure for confirming the registration (re-registration) of the medicinal product. The expert assessment report shall be prepared in accordance with Appendices No. 13-15 and 23 to these Rules.
(Clause 136 as amended by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No. 36)
137. The authorized body (expert organization) of the state of recognition, based on the results of the examination of the medicinal product, within a period not exceeding 20 working days from the date of receipt of the final expert report on the assessment of the reference state, shall prepare, approve, and, using the tools of the integrated system, send to the authorized body (expert organization) of the reference state a conclusion on the possibility or impossibility of recognizing the expert report on the assessment of the reference state in the form in accordance with Appendix No. 18 to these Rules.
138. Proposals from authorized bodies (expert organizations) of the reference state and recognition states to amend the summary of product characteristics, instructions for medical use, packaging layouts of the medicinal product, or other registration dossier documents, if the applicant agrees with them, cannot serve as grounds for refusing to confirm the registration (re-registration) of the medicinal product.
139. If, based on the results of the expert assessment of the medicinal product in the reference state, it is established that the benefit-risk ratio is assessed positively and the registration dossier, taking into account the amendments made, meets the established requirements:
a) the authorized body (expert organization) of the reference state, within a period of no more than 10 working days from the date of receipt of the expert assessment report, issues to the applicant an indefinite registration certificate for the medicinal product in the form in accordance with Appendix No. 17 to these Rules, the approved SmPC, instructions for medical use, a regulatory document on quality, packaging layouts of the medicinal product, the expert assessment report (as well as the approved SmPC, instructions for medical use, and packaging layouts of the medicinal product in the official language of the reference state, if this requirement is present in the legislation of the Member State) and, if necessary, an agreed risk management plan;
(as amended by decisions of the Council of the Eurasian Economic Commission of 30.01.2020 No. 9, of 17.03.2022 No. 36)
b) the authorized bodies of the states of recognition, within a period of no more than 10 working days from the date of receipt of the expert assessment report, issue to the applicant perpetual registration certificates for the medicinal product in the form in accordance with Appendix No. 17 to these Rules, as well as, if necessary, approved summary of product characteristics, instructions for medical use, and packaging layouts for the medicinal product in the official language of the states of recognition, if there are relevant requirements in the legislation of these states;
c) the authorized bodies of the member states participating in the registration confirmation (re-registration) procedure, within no more than 10 working days from the date of receipt of the expert assessment report, post the necessary information about the medicinal product and its active pharmaceutical ingredients in the unified register, along with a summary of the agreed risk management plan (if necessary).
(as amended by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No 36)
140. If it is impossible to recognize the expert assessment report prepared by the expert organization of the reference state, the authorized body (expert organization) of the recognizing state shall send in electronic and/or paper form a conclusion on the impossibility of recognizing this expert report, along with the justification for the decision taken by the authorized body (expert organization) of the reference state and the recognizing states participating in the procedure for confirming the registration (re-registration) of the medicinal product, to the applicant and the Expert Committee within the time period specified in paragraph 137 of these Rules.
141. The Expert Committee, within a period not exceeding 60 calendar days from the date of receipt of the conclusion of the authorized body of the recognizing state on the impossibility of recognizing the expert assessment report of the reference state, shall carry out the procedure for considering the disagreements in accordance with the procedure established by the Commission.
The authorized body of the Member State of recognition shall refuse to confirm the registration (re-registration) of a medicinal product if, following the examination of the medicinal product and the dispute resolution procedure conducted by the Expert Committee, it is determined that the expert assessment report prepared by the expert organization of the reference state cannot be recognized by the authorized body (expert organization) of the Member State of recognition for the reasons specified in paragraph 146 of these Rules.
142. When confirming the registration (re-registration) of a medicinal product, the authorized body (expert organization) of the Member State shall analyze the compliance of the registration certificate holder with the conditions related to the registration of the medicinal product set forth in Section VII of these Rules, if these obligations were applied to this registration certificate holder. If new data on the safety and efficacy of the medicinal product is identified, the authorized body may amend the registration conditions and/or introduce new conditions.
During the assessment of the registration dossier of a medicinal product in the process of confirming the registration (re-registration) of a medicinal product by the authorized bodies (expert organizations) of the Member States, the fulfillment by the holder of the registration certificate of the obligations to maintain information on the medicinal product up-to-date in the light of current scientific knowledge is checked, taking into account the conclusions based on the results of assessments and recommendations of the authorized body (expert organization).
143. If the authorized body (expert organization) of the reference state finds during the examination of the medicinal product during confirmation of its registration (re-registration) that the obligations specified in paragraph 142 of these Rules have not been fulfilled for objective reasons and amendments to the registration dossier of the medicinal product are required, then after the reference state has adopted a positive conclusion on confirmation of registration (re-registration) of the medicinal product, the regulatory document on quality, the summary of product characteristics, instructions for medical use and the risk management plan (if applicable) should be updated by initiating the relevant procedure for amending the registration dossier by the registration certificate holder within a period not exceeding 120 working days from the date of sending a request by the authorized body (expert organization) of the reference state on the need to amend the registration dossier.
144. The authorized body (expert organization) of the reference state may allow amendments to the registration dossier of a Type I medicinal product in accordance with Appendix No. 19 to these Rules when confirming the registration (re-registration) of the medicinal product, in order to avoid the need to submit an additional application for amendments to the registration dossier.
145. Based on pharmacovigilance data, as well as taking into account the circumstances specified in paragraphs 143 and 144 of these Rules, when confirming the registration (re-registration) of a medicinal product, the authorized body of the reference state, following the results of an expert examination of the medicinal product, may decide to issue a registration certificate with a validity period of 5 years, with the need for subsequent confirmation of registration (re-registration) upon expiration of the specified validity period of the registration certificate.
146. The grounds for refusal to confirm (re-register) a medicinal product by the authorized body of the reference state and for the authorized body of the state to recognize the expert assessment report are:
a) the persistence of the following serious health risks associated with the use of the medicinal product at the time of confirmation of registration (re-registration):
a proven unfavorable benefit-risk ratio or a demonstrated lack of therapeutic efficacy when the conditions of use of the medicinal product described in the approved SmPC are met;
facts established based on pharmacovigilance data indicating an unfavorable benefit-risk ratio (including a significant excess of the reporting frequency of certain adverse reactions compared to the data specified in the approved SmPC);
a discrepancy between the qualitative and quantitative composition of the medicinal product and the declared one, or repeated discrepancies in the quality of the medicinal product during its circulation on the Union market with the declared one at the time of its registration;
inaccurate or out-of-date data in the registration dossier accompanying the application for confirmation of registration (re-registration);
b) failure by the registration certificate holder to address concerns or to respond within the allotted time to questions that arose during the examination of the medicinal product;
c) failure by the registration certificate holder to fulfill pharmacovigilance obligations or obligations under the conditional registration procedure.
IX. Amendments to the registration dossier
of a registered medicinal product
147. Following registration of a medicinal product in the reference state, the marketing authorization holder must make any amendments to the registration dossier of the registered medicinal product (hereinafter referred to as "amendments") that may be necessary to ensure that the production and quality control of the medicinal product comply with current generally accepted scientific methods.
Such amendments must be approved by the authorized body of the Member State in which the medicinal product is registered (or this authorized body must be notified of them in accordance with the approved procedure). Amendments to the registration dossier of a medicinal product must be initiated by the applicant through the authorized body (expert organization) of the same reference state that registered the medicinal product.
Amendments to the registration dossier of a medicinal product registered under the mutual recognition procedure in the reference state are permitted prior to the commencement of the recognition procedure in the designated states in accordance with paragraph 66.1 of these Rules.
148. The Marketing Authorization Holder is obliged to notify the authorized body of the Member State of any new information that may require amendments to the documents and data contained in the marketing authorization for the medicinal product.
The Marketing Authorization Holder must promptly notify the authorized body of the Member State of any prohibition or restriction on the medical use of the medicinal product imposed by the authorized bodies of any state where the medicinal product is marketed, and of all other information that may impact the benefit-risk assessment of the medicinal product. The information must include both positive and negative results of clinical trials or other studies (including those containing evidence obtained based on real-world clinical practice data) for all indications and in all patient groups, regardless of their inclusion in the registration dossier, as well as data on the use of the medicinal product if such use does not comply with the registration conditions.
149. The Marketing Authorization Holder must ensure that the information on the medicinal product complies with current scientifically based medical standards, including expert opinions and recommendations of authorized bodies in the field of medicinal product circulation in other countries.
150. To ensure continuous assessment of the benefit-risk balance of a registered medicinal product, the authorized body of a Member State (including at the request of an expert organization) has the right to request from the Marketing Authorization Holder for the registered medicinal product data confirming that the benefit-risk balance of the registered medicinal product remains favorable. The Marketing Authorization Holder (MAH) is obligated to submit the necessary materials to this authorized body (expert organization) as soon as possible, but no later than 20 business days from the date of receipt of the relevant request.
The authorized body of a member state (including at the request of an expert organization) has the right to request a copy of the pharmacovigilance system master file from the MAH for a registered medicinal product. The MAH must submit the corresponding copy within 10 business days from the date of receipt of this request.
151. Amendments to the registration dossier of a registered medicinal product must not alter the positive benefit-risk balance of the medicinal product.152. Amendments to the registration dossier of a registered medicinal product are made in accordance with the classification of amendments made to the registration dossier of a registered medicinal product and the rules for making them in accordance with Appendices No. 19 and 20 to these Rules. The review of amendments to the registration dossier of medicinal products is carried out in accordance with Appendix No. 20 to these Rules.
The applicant has the right to withdraw their application at any time before the end of the procedure for amending the registration dossier of a registered medicinal product by notifying the authorized body of the Member State in which the application is being reviewed of the withdrawal in writing.
If an application is withdrawn, the authorized body of the Member State where the application is being considered shall cease its consideration on the merits and return the original documents and/or information submitted with the application to the applicant.
An expert report on the assessment of changes to the registration dossier of a medicinal product shall be prepared by the expert organization of the reference State based on the results of this assessment in accordance with Appendix No. 21 to these Rules in the event of Type I changes, with the exception of administrative changes.
(paragraph introduced by Decision No. 36 of the Council of the Eurasian Economic Commission dated 17.03.2022)
To make a decision on the possibility of introducing an administrative change to the registration dossier, the applicant must, along with the application for this change, submit, in hard copy or electronic form, confirmation from the authorized body (expert organization) of the reference state that the corresponding version (sequence) of the registration dossier is valid and attached to the electronic registration dossier.
Following the results of the expert organization's review of Type II changes in the reference state, if the requested change is approved, the expert assessment report must be updated in accordance with Appendix No. 16 to these Rules.
Following the review of Type II amendments by the expert organization of the reference state, in the event of disapproval of the proposed amendment, information containing the experts' reasoned position is sent to the authorized body.
In order to update information on the medicinal product based on the review of Type II amendments made to the registration dossier of the medicinal product, brought into compliance with the requirements of the Union, the expert organization of the reference state may establish one or more additional requirements in the final expert report on the assessment of the medicinal product in accordance with Clause 116 of these Rules.
(paragraph introduced by Decision No. 114 of the Council of the Eurasian Economic Commission dated 20.10.2023)
153. If the authorized body (expert organization) approves amendments to the registration dossier of a medicinal product, the applicant shall be issued a new registration certificate under the previous number for the remaining validity period of the medicinal product registration if the amendments affect the information and data of the registration certificate. A record of each amendment made shall be made in the unified register, indicating its details and the section of the dossier to which the amendment was made.
154. If amendments to the registration dossier of a medicinal product occur 90 calendar days or less before the expiration of the registration certificate, amendments may be made during the examination of the medicinal product upon confirmation of its registration (re-registration).
155. When making changes to the registration dossier of a medicinal product registered under the mutual recognition procedure, the applicant must submit to the authorized body (expert organization) of the reference state a list of the dates of filing the relevant applications for amendments to the registration dossier of the medicinal product in the recognition states and documents confirming payment of the fee (duty) for making changes to the registration dossier of the medicinal product (and its expert examination, if necessary) in the cases and according to the procedure established by the legislation of the recognition states, indicating the procedure numbers for making changes in accordance with Appendix No. 19 to these Rules that were carried out in the recognition states.
When changing the registration certificate holder in all or several (one) Member States that have registered the medicinal product, the applicant shall submit to the authorized body (expert organization) of these Member States an application for amendments in accordance with Appendix No. 2 to these Rules and the relevant documents from Module 1 of the registration dossier.
In accordance with the requirements of the legislation of a Member State, the documents specified in this paragraph may be submitted using electronic document management without the additional submission of relevant documents and information on paper, signed and/or certified by the applicant's electronic signature, in cases stipulated by these Rules.
156. When conducting an expert examination of a medicinal product and introducing changes to the registration dossier of the medicinal product, the expert organization and the authorized body of the reference state have the right to send the applicant a written and/or electronic request for missing additional information, necessary explanations, or clarifications concerning the submitted documents and data in the registration dossier (including proposals for amendments to the summary of product characteristics, instructions for medical use, medicinal product packaging layouts, quality regulatory document, or other documents of the registration dossier).
The applicant's response to this request must be submitted within 90 business days. The time required for the applicant to submit documents requested by the authorized body or expert organization during the amendment and review process for the medicinal product is not included in the review and amendment process.
If the applicant fails to submit the requested documents and data within the specified timeframe, the review and amendment process for the medicinal product's registration dossier will be terminated. The authorized body (expert organization) will notify the applicant of the decision made within 14 business days of the date of such decision in written and/or electronic form.
157. When amendments are made to the registration dossier in terms of amendments to the instructions for medical use of a medicinal product, the authorized body shall approve and issue new instructions for medical use to the applicant.
158. In the event of confirmation of registration (re-registration) of a medicinal product or amendments being made to the registration dossier, manufacture of the medicinal product is permitted for 180 calendar days from the date of confirmation of registration (re-registration) or amendments being made to the registration dossier in accordance with the information contained in the registration dossier documents of the medicinal product, until the date of confirmation of registration (re-registration) or amendments being made, with the exception of:
urgent safety restrictions introduced by the registration certificate holder or the authorized body, in accordance with paragraph 4.1.4 of Appendix No. 19 to these Rules;
A decision by a Member State's authorized body on the impossibility of further production of a medicinal product in accordance with previously approved (agreed upon) documents and information in the registration dossier.
The import, simultaneous sale, and medical use of a medicinal product are permitted until the expiration of its expiration date (shelf life), consistent with the documents and information in the registration dossier before and after amendments, provided this does not conflict with the requirements of the Union's good pharmacovigilance practice rules approved by the Commission.
(Clause 158 as amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated March 17, 2022)
X. Suspension, revocation (cancellation) of a registration
certificate, or restriction of use, or amendment of the terms of a registration
certificate
159. The authorized body shall suspend the registration certificate or restrict the use of a medicinal product in the following cases:
there are documented facts of discrepancy between the qualitative and quantitative composition of released batches of the medicinal product and the declared composition;
the medicinal product is dangerous (causes serious or irreparable harm to human health (the justification for the seriousness or irreparability of the harm to health must be supported by an expert opinion of the authorized body (expert organization) with reference to documentary evidence));
an unfavorable benefit-risk ratio has been proven or documented insufficient therapeutic efficacy of the medicinal product has been identified under the conditions of its use described in the approved SmPC;
a positive benefit-risk ratio has not been confirmed during the reassessment of the benefit-risk ratio, conducted annually by the authorized body (expert organization) in accordance with paragraph 117 of these Rules;
the registration dossier contains inaccurate documents and data;
The manufacturer failed to correct the nonconformities in production and control methods identified during the inspection, as stated in the registration dossier, within the timeframes agreed upon with the authorized body (expert organization);
The registration certificate holder has failed to fulfill its pharmacovigilance obligations;
The registration certificate holder has failed to fulfill its obligations in accordance with paragraphs 116 and 118 of these Rules, as established by the authorized body (expert organization).
In cases of suspension of the registration certificate, as specified in paragraphs two through four of this paragraph, the authorized body (expert organization) shall send the registration certificate holder a request to amend the relevant documents of the registration dossier, specifying the deadline for compliance.
160. The decision to revoke (cancel) the registration certificate of a medicinal product and to exclude the medicinal product from the Unified Register shall be made by the authorized body (expert organization) in the event of:
a) the filing by the holder of the registration certificate of the medicinal product or a legal entity authorized by the holder of the registration certificate of the medicinal product of an application to cancel the registration of the medicinal product;
b) the failure of the holder of the registration certificate of the medicinal product to comply with the requirements of the authorized body (expert organization) specified in paragraphs two through nine of clause 159 of these Rules;
c) the submission by the authorized body (expert organization) of a conclusion on the failure of the holder of the registration certificate to eliminate the nonconformities in production and control methods identified during the inspection, as declared in the registration dossier, within the prescribed timeframe.
161. In the cases specified in paragraphs 159 and 160 of these Rules, the authorized bodies of Member States shall take appropriate measures (actions) to ensure that the supply of the medicinal product is stopped and that the medicinal product is withdrawn from circulation.
162. In exceptional cases, for a limited period of time, the authorized body may permit the circulation of a medicinal product whose sale is prohibited or which has been withdrawn from the market, exclusively for its controlled use in patients who used this medicinal product for vital indications.
(as amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated 17 March 2022)
XI. Conditions for the circulation of medicinal products in Member States
163. Medicinal products registered in accordance with these Rules and included in the unified register shall be sold within the Union within the Member States in which they are registered.
164. Medicinal products registered in Member States that have not been brought into compliance with Union requirements shall be sold after December 31, 2025, within the territory of that Member State until the expiration of their expiration date (shelf life).
165. Medicinal products whose registration certificates have expired may be sold in Member States until the expiration of their expiration date (shelf life), if they were manufactured before the expiration of their registration certificate.
XII. Obligations of Marketing Authorization Holders
166. The Marketing Authorization Holder shall promptly provide complete information upon request from the authorized body of any Member State in which the medicinal product is registered.
167. The Marketing Authorization Holder shall notify the authorized body of the Member State of the planned cessation of production or sale of the medicinal product on the Union market, stating the reasons, at least 60 calendar days prior to such cessation of production or sale.
168. In the event of a change of Marketing Authorization Holder in the Reference State or the State of Recognition, the new Marketing Authorization Holder shall provide documentary justification for such change (transfer) and confirmation of the ability to interact with Marketing Authorization Holders in other Member States to ensure the proper performance of all Marketing Authorization Holder duties.
169. During the validity period of a registration certificate for a medicinal product issued for an unlimited period, the benefit-risk ratio shall be periodically assessed based on pharmacovigilance, as well as to update information on the medicinal product (taking into account the conclusions of the assessment results and recommendations of the authorized body (expert organization) of the Member State or the Expert Committee).
(Clause 169 as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated October 20, 2023)
XIII. Procedure for bringing the registration dossier of a medicinal product registered under the rules of a Member State into compliance with the requirements of the Union
(as amended by Decision No. 36 of the Council of the Eurasian Economic Commission of 17 March 2022)
170. Registration dossiers of medicinal products registered in Member States must be brought into compliance with Union requirements by December 31, 2025, in accordance with this procedure.
171. Bringing a registration dossier into compliance with Union requirements includes submitting the registration dossier documents for the registered medicinal product in the format of a common technical document in accordance with Appendix No. 1 to these Rules.
When initiating the procedure for bringing the medicinal product into compliance with the requirements of the Union, the applicant shall submit to the authorized body (expert organization) of the reference state a written confirmation that the documents and data contained in the submitted updated registration dossier in the format of a common technical document correspond in their content to the data of the registration dossier of the medicinal product registered in the Member State(s) and do not contain changes to the registration dossier that affect the quality, efficacy, safety or benefit-risk ratio of the medicinal product, in the form of a document "For the attention of experts" provided for in paragraph 1.0 of Appendix No. 1 to these Rules.
(as amended by decisions of the Council of the Eurasian Economic Commission of 23.04.2021 No. 34, of 17.03.2022 No. 36, of 20.10.2023 No. 114)
Bringing the registration dossier into line with the requirements of the Union in terms of bringing draft packaging layouts, general characteristics of the medicinal product, instructions for medical use (package insert), and regulatory documents on quality into line with the acts of the Commission is not considered a change requiring a reassessment of the benefit-risk ratio, and is not a change affecting the conformity of the content of the registration dossier data being brought into line with the requirements of the Union with the content of the registration dossier data of the registered medicinal product.
(paragraph introduced by Decision No. 34 of the Council of the Eurasian Economic Commission dated 23.04.2021)
In accordance with the requirements of the legislation of a Member State, the documents specified in the first and second paragraphs of this clause may be submitted using electronic document management without the additional submission of relevant documents and information on paper, signed and/or certified by the applicant's electronic signature, in cases stipulated by these Rules.
172. When bringing the medicinal product into compliance with Union requirements, the applicant may simultaneously amend the registration dossier of the registered medicinal product. In this case, the procedure for making such amendments and assessing the dossier for compliance with acts within the law of the Union shall be carried out in accordance with Appendices No. 19 and 20 to these Rules.
The list of amendments that may be introduced by the applicant concurrently with the harmonisation with Union requirements, in accordance with this paragraph, is specified in Appendix VI to Appendix No. 19 to these Rules and contains unclassified Type IB amendments. The authorized body (expert organization) of the reference state has the right to review the amendments introduced concurrently within the timeframes stipulated for the harmonisation with Union requirements procedure.
Upon completion of the harmonisation procedure for the registration dossier in the reference state with Union requirements, the applicant may make procedural amendments in accordance with Appendices No. 19 and 20 to these Rules prior to the initiation of the mutual recognition procedure in the state(s) of recognition (prior to the submission of the relevant application to the authorized body (expert organization) of the recognition states).
173. The procedure for bringing a medicinal product's registration dossier into compliance with Union law shall not exceed 70 working days from the date of submission of the relevant application for bringing the registration dossier into compliance with Union law.
174. If a medicinal product is registered in more than one Member State, the applicant shall select one of them as the reference state, to whose authorized body (expert organization) the applicant shall submit the application, documents, and registration dossier data in accordance with paragraph 175 of these Rules. If the authorized body (expert organization) of the reference state makes a positive decision to bring the medicinal product's registration dossier into compliance with the acts included in Union law, the procedure for bringing the medicinal product's registration dossier into compliance in the recognition states shall be carried out according to the mutual recognition of registration model, in accordance with the procedures specified in paragraphs 66–82 of these Rules.
Amendments to the registration dossier of a registered medicinal product in the reference state are permitted in accordance with Appendices No. 19 and 20 to these Rules prior to the initiation of the mutual recognition procedure in the state(s) of recognition.
Simultaneous initiation of the mutual recognition procedure in several states of recognition is permitted.
175. To bring the registration dossier of a medicinal product into compliance with the requirements of the Union and to continue circulation of the medicinal product in the territories of the Member States in which it is registered, the applicant shall submit to the authorized body (expert organization) of the reference state in which the medicinal product is registered:
an application on paper or as an electronic document signed with an electronic signature, in the form set out in Appendix No. 2 to these Rules;
documents confirming payment of the fee (duty) for bringing the medicinal product into compliance with the requirements of the Union in the cases and according to the procedure established in accordance with the legislation of the recognition states, on paper or as an electronic document;
modules 1-3 of the registration dossier of the medicinal product on electronic media and/or in the form of electronic documents in accordance with Appendices No. 1-5 to these Rules.
In this case, Module 2 of the registration dossier may be presented in the form of overview sections with the necessary updates of changes (in the form of appendices) in the corresponding sections 2.3 - 2.5 of Module 2 of the registration dossier.
If there are differences in the registration dossier of a medicinal product, based on which the medicinal product is registered in different Member States, in dosages and manufacturing sites, the applicant shall provide updated information on the existing differences and their justification in Module 1 of the registration dossier in the form of a document "For the Information of Experts" as provided for in paragraph 1.0 of Appendix No. 1 to these Rules.
If there are different manufacturing sites, comparative studies must be submitted to the authorized body (expert organization) of the Member State.
If there are differences in the indications for use, dosages, and routes of administration of a medicinal product in different Member States, the applicant shall provide updated information on the existing differences and their justifications in Sections 2.4 and 2.5 of Module 2 of the medicinal product registration dossier, and shall provide reports on the relevant studies in Modules 4 and/or 5 of the medicinal product registration dossier.
In accordance with the requirements of the legislation of a Member State, the submission of the documents specified in paragraphs two through four of this clause may be carried out using an electronic document management system without the need to submit the relevant documents and information on paper, signed and/or certified by the applicant's electronic signature.
Data from preclinical and clinical studies conducted in accordance with the requirements of the legislation of the Member States are presented in modules 4 and 5 of the registration dossier of the medicinal product (without the mandatory alignment of reports on preclinical (non-clinical) studies and clinical studies (tests) of the medicinal product with the rules for the preparation of such reports established by acts of the Union bodies) in the form of relevant reports.
The applicant has the right to withdraw their application at any time prior to the completion of the harmonisation procedure with Union requirements by notifying the authorized body of the Member State where the application is being reviewed in writing.
In the event of withdrawal of the application, the authorized body of the Member State where the application is being reviewed shall cease consideration of the application on the merits and return the original documents and/or information submitted with the application to the applicant.
When conducting an expert review of the registration dossier of a medicinal product as part of the harmonisation procedure with Union requirements, if the required data are missing from Modules 4 and 5 of the registration dossier of the medicinal product, or if new relevant safety information on the medicinal product is available following the review, the authorized body (expert organization) of the reference state may impose additional obligations on the registration certificate holder, as provided for in Section VII of these Rules (including a limited (urgent) validity period of the registration certificate). (Clause 175 as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated 20.10.2023)
175(1). If a medicinal product is registered in one Member State and is intended for circulation only within its territory, the applicant may submit, in the official language(s) of that Member State or in another language (if so provided for by the legislation of that Member State), without translation into Russian (if Russian is not the official language of that Member State), only Modules 1–3 of the registration dossier of the medicinal product (in electronic form in accordance with Appendices Nos. 1–5 to these Rules).
Module 2 of the registration dossier of the medicinal product shall be submitted in the form of summaries (Sections 2.3–2.5), with updated changes included as an appendix to the original documents of the registration dossier.
If documents from Modules 4 and 5 of the registration dossier of a medicinal product are available, the applicant has the right to submit them as part of the registration dossier of the medicinal product without submitting Sections 2.4 and 2.5 of Module 2 of the registration dossier of the medicinal product. The authorized body (expert organization) has the right to request documents from Modules 4 and 5 of the registration dossier upon request. (Clause 175(1) as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
176. The authorized body (expert organization) of the reference Member State shall assess the completeness, completeness, and correctness of the submitted documents of the registration dossier of the medicinal product within 10 working days before sending the registration dossier materials for expert review. The applicant is given no more than 90 working days, outside the expert review period, to submit missing materials from the medicinal product registration dossier based on comments from the authorized body (expert organization) of the reference state. (as amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated March 17, 2022)
The authorized body (expert organization) of a Member State shall reject an application to bring the registration dossier of a medicinal product into compliance with Union requirements in the event of failure to submit missing materials from the registration dossier of the medicinal product in response to comments from the authorized body (expert organization) of the reference State and/or failure to confirm payment of the fee (duty) for bringing the registration dossier of the medicinal product into compliance with Union requirements in the cases and according to the procedure established by the legislation of the reference State.
The authorized body's (expert organization's) request to the applicant must be transmitted electronically via telecommunications channels and is considered received one calendar day after the date of its submission. (paragraph introduced by Decision No. 36 of the Council of the Eurasian Economic Commission dated 17.03.2022)
The applicant's response shall be assessed within five working days from the date of receipt of the applicant's response. (paragraph introduced by Decision No. 36 of the Council of the Eurasian Economic Commission dated March 17, 2022)
The examination specified in this clause shall be carried out within a period not exceeding 45 working days from the date of the assessment of the completeness, completeness, and correctness of the documents submitted in the registration dossier, or from the date the expert organization receives the relevant assignment to conduct the examination. (paragraph introduced by Decision No. 36 of the Council of the Eurasian Economic Commission dated 17.03.2022)
177. When conducting an expert examination of a medicinal product during the procedure for bringing the medicinal product's registration dossier into compliance, the authorized body (expert organization) of the reference state may send the applicant a written and/or electronic request for additional information, necessary clarifications, or clarifications regarding the submitted documents and data in the medicinal product's registration dossier (including proposals for amendments to the summary of product characteristics, instructions for medical use, medicinal product packaging layouts, quality regulatory documents, or other documents in the registration dossier).
After the initial request, subsequent requests are permitted only if additional questions arise regarding the information provided by the applicant in response to the previous request. The total response time for requests shall not exceed 180 business days. (paragraph introduced by Decision No. 114 of the Council of the Eurasian Economic Commission dated 20.10.2023)
The applicant's response to this request shall not exceed 90 business days. The time required for the applicant to submit documents requested by the authorized body or expert organization during the expert examination of the medicinal product is not included in the timeframe for the expert examination of the medicinal product when bringing the registration dossier of the medicinal product into compliance with the requirements of the Union. (as amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated 17.03.2022)
If the applicant fails to submit the requested documents and data within the specified timeframe, the expert examination and the procedure for bringing the registration dossier of the medicinal product into compliance with the requirements of the Union shall be terminated. The authorized body (expert organization) of the reference state shall notify the applicant and the authorized bodies (expert organizations) of the states of recognition (if any) of the decision taken within 14 business days from the date of the decision in written and/or electronic form.
178. Based on the results of the expert examination of the registration dossier of a medicinal product, the authorized body (expert organization) of the reference state shall prepare and approve an expert assessment report in the form set out in Appendix No. 16 to these Rules, based on the expert examination of the documents of the registration dossier of the medicinal product submitted by the applicant in accordance with paragraphs 175 and 175(1) of these Rules, including an assessment of the clarifications received from the applicant, documents, and data submitted in response to the request of the expert organization or authorized body.
(as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
When conducting an expert examination of the registration dossier of a medicinal product as part of the procedure for bringing the registration dossier of a medicinal product into compliance with the requirements of the Union, the benefit-risk ratio shall not be reassessed, except in the cases specified in paragraph 181 of these Rules.
179. The authorized body of the reference state refuses to bring the registration dossier of a medicinal product into compliance with the requirements of the Union if, based on the results of the examination of the registration dossier of the medicinal product, it is established that its quality has not been confirmed, or, in accordance with the second part of paragraph 178 of these Rules, an unfavorable benefit-risk ratio has been identified.
180. Based on the results of the examination of the registration dossier of the medicinal product and subject to a positive decision on the compliance of the registration dossier of the medicinal product with the requirements of these Rules, the authorized bodies of the Member States in which the drug is registered and to which an application has been submitted to bring the registration dossier of the medicinal product into compliance with the requirements of the Union, within a period not exceeding 10 working days from the date of receipt of the expert assessment report, issue to the applicant a registration certificate for the medicinal product in the form in accordance with Appendix No. 17 to these Rules, the approved SmPC, instructions for medical use, a regulatory document on quality control, packaging layouts of the medicinal product (if necessary, the applicant is issued an expert assessment report, as well as SmPC, instructions for medical use and packaging layouts of the medicinal product approved in the official language of these Member States, if there are relevant requirements in the legislation of these Member States), an agreed risk management plan (if necessary) and enter information on the registration of the medicinal product into the unified register.
When harmonizing with Union requirements, a medicinal product registered in accordance with the legislation of a Member State for five years or more is issued an indefinite registration certificate if the medicinal product is intended to be marketed only in that Member State. Following the harmonizing procedure, a registration certificate for a medicinal product registered in accordance with the legislation of the Member States specified in the harmonizing application and registered in the reference state for five years or more is issued for an indefinite period as part of the harmonizing procedure in accordance with Section XIII of these Rules. If less than five years have passed since the medicinal product's registration in the reference state, the authorized body of the reference state, following the process of bringing the medicinal product into compliance with Union requirements, issues the applicant a registration certificate valid for five years. Registration (re-registration) of the medicinal product will need to be confirmed upon expiration of the registration certificate. In this case, the authorized bodies of the Member States to which the application for compliance with Union requirements has been submitted will issue the applicant a registration certificate with the validity period established by the reference state. (as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated 20.10.2023)
After the registration dossier of a medicinal product has been brought into compliance with the requirements of the Union, production of the medicinal product in Member States and third countries is permitted with a registration certificate issued in accordance with the legislation of the Member State, within 180 calendar days from the date the registration dossier was brought into compliance with the requirements of the Union (the date of compliance is considered to be the date the relevant information is entered into the unified register).
(This paragraph was introduced by Decision No. 9 of the Council of the Eurasian Economic Commission dated 30.01.2020; as amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated 17.03.2022)
The import, simultaneous sale, and medical use of medicinal products specified in the third paragraph of this clause are permitted until the expiration of their shelf life, provided they comply with the documents and information in the registration dossier approved in accordance with the legislation of the Member States and the registration dossier brought into compliance with the requirements of the Union.
(As amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated 17.03.2022)
180(1). In order to harmonize the requirements imposed on the documents of the registration dossier of a medicinal product registered in different Member States (in the event of differences in the information in the registration dossier of a medicinal product registered in accordance with the legislation of Member States), as part of the procedure for bringing it into conformity with the requirements of the Union, it is permitted to make significant changes to the registration dossier of a medicinal product in the reference state in accordance with Appendix V to Appendix No. 19 to these Rules, if the registration dossier of a medicinal product registered in accordance with the legislation of Member States contains documents and data that require changes. In this case, the authorized bodies (expert organizations) of the Member States in which the given drug is registered and to which an application for bringing it into conformity with the requirements of the Union has been submitted, make a decision on bringing the registration dossier of the medicinal product into conformity with the requirements of the Union based on the assessment of the documents specified in paragraph 69 of these Rules, in accordance with paragraph 180 of these Rules. In such a case, the applicant shall submit to the authorized body (expert organization) of the reference state the registration dossier of the medicinal product and information on any differences in the registration dossier of the medicinal product registered in accordance with the legislation of the Member States, and the justifications for these differences, in the form of a document "For the Information of Experts" provided for in paragraph 1.0 of Appendix No. 1 to these Rules. (Clause 180(1) introduced by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
181. Medicinal products may be applied for registration under the mutual recognition procedure in Member States in which the medicinal product has not been registered in accordance with the legislation of the Member States, after bringing its registration dossier into compliance with the requirements of the Union in the reference state. (as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated 20.10.2023)
182. As part of the procedure for bringing the medicinal product into compliance with the Union requirements for subsequent registration under the mutual recognition procedure in a Member State in which the medicinal product has not been registered or submitted for registration in accordance with the legislation of the Member State, the applicant shall submit to the authorized body (expert organization) of the reference State:
an application on paper or as an electronic document signed with an electronic signature, in the established form in accordance with Appendix No. 2 to these Rules;
documents confirming payment of the fee (duty) for bringing the medicinal product into compliance with the Union requirements in the cases and according to the procedure established in accordance with the legislation of the recognition States, on paper or as an electronic document;
Modules 1–5 of the registration dossier in accordance with Appendices Nos. 1–5 to these Rules in the event of subsequent registration under the mutual recognition procedure in Member States in which the medicinal product has not been registered or submitted for registration in accordance with the legislation of the Member State.
In accordance with the requirements of the legislation of the Member State, the documents specified in paragraphs two through four of this clause may be submitted using electronic document management without the additional submission of relevant documents and information on paper, signed and/or certified by the applicant's electronic signature.
All available data from preclinical and clinical studies conducted in accordance with the legislation of Member States are presented in accordance with these Rules in Modules 4–5 of the registration dossier as existing reports, without the need to align them with the requirements for the formatting of reports on preclinical (non-clinical) studies and clinical studies (trials) stipulated by the rules of good laboratory practice and good clinical practice, as well as with the Rules for Conducting Bioequivalence Studies of Medicinal Products. The Member State to which the registration dossier is submitted for aligning it with Union requirements acts as the reference state in this case. (Clause 182 as amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated 17.03.2022)
183. If it is necessary to prepare an expert assessment report for the mutual recognition procedure in a state in which the medicinal product has not been registered or submitted for registration in accordance with the legislation of a Member State, a reassessment of the benefit-risk ratio of the medicinal product and an expert examination of the medicinal product shall be carried out in accordance with the procedures established in Section V of these Rules.
XIV. Transitional Provisions
184. Registration (expert assessments for registration), confirmation of registration (re-registration), and amendments to the registration dossier of medicinal products submitted for registration (expert assessments for registration), confirmation of registration (re-registration), and amendments to the registration dossier of medicinal products in Member States before July 1, 2021 (in the Russian Federation, before December 31, 2020) shall be carried out in accordance with the legislation of the Member States.
At the applicant's request, registration of a medicinal product submitted for registration (expert assessments for registration) before July 1, 2021 (in the Russian Federation, before December 31, 2020) may be carried out in accordance with the legislation of the Member State without regard to the requirements of these Rules.
The registration dossier of a medicinal product registered in accordance with paragraphs one and two of this clause must be brought into compliance with the requirements of the Union by December 31, 2025.
(Clause 184 as amended by Decision of the Council of the Eurasian Economic Commission dated March 5, 2021, No. 14)
185. Confirmation of registration (re-registration) and amendments to the registration dossier of a medicinal product registered in Member States in accordance with their legislation and that has not undergone the procedure for bringing it into compliance with the requirements of the Union shall be carried out in accordance with the legislation of the Member States by December 31, 2025.
(Clause 185 as amended by Decision of the Council of the Eurasian Economic Commission dated March 5, 2021, No. 14)
186. Simultaneous sale of a medicinal product in previously and newly approved packaging with previously and newly approved instructions for medical use is permitted until the expiration date (validity period) (storage) of a medicinal product.
The sale of medicinal products released into circulation in a Member State prior to the medicinal product's registration dossier being brought into compliance with the Union's requirements is permitted until the expiration of their shelf life.
XV. Special Cases
187. If the medicinal product's dosage form includes components that are medical devices, information on the registration of the medical device must be included in the registration dossier. Furthermore, if the device is complex in structure and may be a comprehensive delivery system, an expert opinion on the safety, quality, and efficacy of the medical device, in terms of its impact on the clinical characteristics of the medicinal product as a whole, must also be included in the medicinal product's registration dossier.
188. Amendments to the registration dossier of vaccines due to changes in the strain composition of influenza vaccines, as well as the registration of pandemic and pre-pandemic influenza vaccines and amendments to their registration dossier, are carried out in accordance with Appendix No. 24 to these Rules.
(Clause 188 introduced by Decision No. 55 of the Council of the Eurasian Economic Commission dated June 14, 2018)
Appendix No. 1
to the Rules for Registration
and Examination of Medicines
for Medical Use
REQUIREMENTS
FOR REGISTRATION DOSSIER DOCUMENTS (IN THE FORMAT OF A GENERAL
TECHNICAL DOCUMENT)
dated January 30, 2020 No. 9, dated March 5, 2021 No. 14, dated April 23, 2021 No. 34,
dated March 17, 2022 No. 36, dated September 23, 2022 No. 141, dated May 22, 2023 No. 60,
dated October 20, 2023 No. 114)
I. General requirements for the registration dossier modules accompanying the application for registration of a medicinal product
The registration dossier may be submitted electronically, without the need for additional paper submission of relevant documents and information.
As part of the procedure for bringing the registration dossier of a medicinal product registered under the national procedure in the member states of the Eurasian Economic Union (hereinafter referred to as the member states or the Union) into compliance with the Rules for the Registration and Examination of Medicinal Products for Medical Use, approved by Decision No. 78 of the Council of the Eurasian Economic Commission dated November 3, 2016 (hereinafter referred to as "bringing it into compliance with the requirements of the Union"), authorized bodies (expert organizations) of the member states, based on a risk analysis, may additionally request from the applicant the documents specified in subsection 11.1 of these Requirements for the registration procedure, marked "if necessary."
If the authorized body (expert organization) of a member state issues the document specified in Module 1 of the medicinal product registration dossier only in electronic form, the applicant shall indicate in the relevant section of the medicinal product registration dossier the details of the electronic document necessary for verifying its authenticity on the official website of the issuing body on the Internet.
1. Requirements for the registration dossier documents provided in Module 1: Administrative Information
1.0. Cover letter (as in the General Technical Document (hereinafter referred to as the GTD)).
A cover letter must be included in this section.
If necessary, a "For the Experts' Information" document may be submitted as an attachment to the cover letter, providing more detailed information for the purpose of improving navigation (e.g., hyperlinks, volume locations, etc.). For version (sequence) 0000 of the electronic registration dossier, when initiating the procedure for bringing it into compliance with Union requirements, the applicant, in the "For the Experts' Information" document, provides a written guarantee that the documents and data contained in the submitted updated registration dossier of the medicinal product in the general technical document format correspond in content to the data in the registration dossier of the registered medicinal product and do not contain changes that affect the safety, efficacy, quality, or benefit-risk balance of the medicinal product.
(as amended by Decision of the Council of the Eurasian Economic Commission dated October 20, 2023, No. 114)
1.1. Contents.
The complete contents of Modules 1-5 of the registration dossier must be submitted.
1.2. General Documentation:
1.2.1. The application for registration of a medicinal product (on paper or as an electronic document created in *.doc, *.docx, and *.pdf formats and signed with an electronic signature) shall be completed using the form in Appendix No. 2 to these Rules.
(Clause 1.2.1 as amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated March 17, 2022)
1.2.2. Documents confirming payment for expert work and/or payment of the registration fee (duty) in accordance with the legislation of the Member State registering the medicinal product (unless the legislation of the Member State prohibits the applicant from providing documents that are in the possession of or can be obtained independently by the authorized body).
1.2.3. A copy of the medicinal product certificate in the format recommended by the World Health Organization, issued by the authorized body of the manufacturing country (if any).
If such a certificate is unavailable, a document confirming registration in the manufacturing country and/or in the country holding the registration certificate for the medicinal product (if any).
If there is no registration in the manufacturing country or the country holding the registration certificate for the medicinal product, an explanatory note justifying the lack of registration data shall be submitted.
1.2.4. A translation into Russian and a copy of the expert report of the authorized body for registration of a medicinal product in the country of manufacture or in the country holding the registration certificate for the medicinal product (if any). Submission is not mandatory as part of the procedure for bringing it into compliance with Union requirements.
1.2.5. Conclusion (recommendation) of the authorized body (authorized organization) of a Member State following the preliminary scientific consultation regarding this medicinal product in Member States (if any).
1.2.6. Recommendation of the Expert Committee on Medicinal Products following the preliminary scientific consultation regarding this medicinal product, including a conclusion on the rationality of the combination of active ingredients of the combined medicinal product (if any).
(clause 1.2.6 as amended by Decision of the Council of the Eurasian Economic Commission dated 22.05.2023 No. 60)
1.3. General characteristics of the medicinal product (hereinafter referred to as SmPC), instructions for medical use (package insert) (hereinafter referred to as IMU), labeling:
1.3.1. Draft summary of product characteristics (SmPC) and general characteristics of medicinal products (GCP), compiled in Russian in accordance with the requirements for the instructions for medical use of a medicinal product and the general characteristics of the medicinal product for medical use, approved by the Eurasian Economic Commission (hereinafter referred to as the Commission). (as amended by decisions of the Council of the Eurasian Economic Commission of 17.03.2022 No. 36, of 22.05.2023 No. 60)
1.3.2. Layouts (full-color copies of the flat original layout, ensuring the reproduction of both the secondary (consumer) and primary (internal) packaging and the labeling of the medicinal product in two-dimensional form, referred to as a "paper copy" or "computer version") of secondary (consumer), primary (internal), and intermediate packaging, compiled in accordance with the labeling requirements for medicinal products for medical use and veterinary medicinal products approved by the Commission. Mock-ups of intermediate packaging, labels, and stickers are submitted if available.
(as amended by Decision No. 141 of the Council of the Eurasian Economic Commission dated September 23, 2022)
1.3.3. Results of user testing of the IMP mock-up (in cases established by Appendix No. 12 to the requirements for the instructions for medical use of a medicinal product and the general characteristics of the medicinal product for medical use, approved by Decision No. 78 of the Council of the Eurasian Economic Commission dated November 3, 2016).
(as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated October 20, 2023)
When presenting the results of user testing, it is necessary to briefly summarize how the testing was conducted and how all necessary changes were incorporated into the final version of the IMP. The summary must be presented in this section of the module, in the following format:
a brief description of the medicinal product;
A brief description of the testing performed or study of individual elements of the IMP (methodology used, explanations of the participant selection criteria, testing language);
Questionnaires used (questionnaires, including instructions for completing them and observation forms);
Original and revised versions of the IMP;
A brief description and discussion of the test results (subject responses, identified problems, and changes made to the relevant sections of the IMP);
Conclusion.
All other details must be provided upon request by the authorized body (expert organization).
1.3.4. Copies of the SmPC and IMP approved by the authorized body of the manufacturing country and/or the country holding the marketing authorization for the medicinal product, with the date of the last revision, certified by an authorized representative of the marketing authorization holder (if available).
1.4. Information on the regulatory status of the drug in other countries (if available).
1.4.1. A list of countries in which the medicinal product has been submitted for registration, registered, denied registration, or suspended, indicating the name of the medicinal product, the registration certificate number and date, its validity period, or the date of the decision to deny registration or suspend the registration certificate. The information provided must be certified by the registration certificate holder.
1.5. Quality Documents:
1.5.1. Certificate of Conformity with the Eurasian Economic Union Pharmacopoeia or European Pharmacopoeia article on spongiform encephalopathy, or a document issued by the authorized veterinary authorities of the country of origin of the raw materials, if pharmaceutical substances of animal origin are used (if applicable).
1.5.2. A letter or a copy of the letter from the active pharmaceutical substance master file holder, signed by the responsible person of the active pharmaceutical substance master file holder, containing an obligation to notify the manufacturer of the medicinal product and the authorized body of the Member State of any changes before any significant changes are made to the active pharmaceutical substance master file, as well as a translation of the specified letter, certified by the marketing authorization holder or notarized.
(clause 1.5.2 as amended by Decision of the Council of the Eurasian Economic Commission dated 22.05.2023 No. 60)
1.5.3. A letter confirming the consent of the pharmaceutical substance master file holder to submit documents from the closed section of the pharmaceutical substance master file upon request of the authorized body of the Member State.
(as amended by Decision of the Council of the Eurasian Economic Commission dated 23.04.2021 No. 34)
1.5.4. A copy of the certificate of conformity of the pharmaceutical substance with the requirements of the European Pharmacopoeia (if available).
1.5.5. A copy of the plasma master file certificate issued by the authorized body of the manufacturing country (if available).
1.5.6. A copy of the vaccine antigen master file certificate issued by the authorized body of the manufacturing country (if available).
1.5.7. A draft regulatory document on quality, prepared in accordance with the Guidelines for drafting regulatory documents on medicinal product quality, approved by Decision of the Board of the Eurasian Economic Commission dated September 7, 2018, No. 151.
(Clause 1.5.7 was introduced by Decision of the Council of the Eurasian Economic Commission dated April 23, 2021, No. 34)
1.6. Manufacturing documents:
1.6.1. Information on the date of issue (decision made by the authorized body) and the registration number in the relevant register of the member state, or a copy of the current document confirming the compliance of the manufacturer (production site producing the finished dosage form and performing quality control) of the medicinal product applied for registration with the Rules of Good Manufacturing Practice of the Eurasian Economic Union, approved by Decision No. 77 of the Council of the Eurasian Economic Commission dated November 3, 2016, and issued by the authorized body of the member state (if applicable in accordance with paragraph 29 of the Rules for the Registration and Examination of Medicinal Products for Medical Use).
Copies of current documents confirming the manufacturer's manufacturing site's compliance with Good Manufacturing Practice (GMP) requirements, issued by authorized bodies of the country in which the manufacturing site is located (manufacturing sites producing the finished dosage form and performing quality control) and/or another authorized body; the internet address of the website registering GMP certificates of conformity issued by the authorized body (e.g., EudraGMP) (if applicable in accordance with paragraph 29 of the Rules for the Registration and Examination of Medicinal Products for Medical Use). (Clause 1.6.1 as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated October 20, 2023)
1.6.2. A copy of the current permit (license) for the manufacture of medicinal products (with appendices), issued by the authorized body of the country in which the manufacturing site(s) producing the finished dosage form and performing release quality control of the medicinal product is located.
For manufacturing sites located in the territories of Member States, instead of the document specified in the first paragraph of this clause, the applicant may submit in the relevant section of the medicinal product registration dossier information contained in the relevant Member State register on the issue date and registration number of the license (permit) for the manufacture of medicinal products issued by the authorized body of the Member State.
(Clause 1.6.2 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
1.6.3. A copy of the inspection report of the manufacturing site (manufacturing sites manufacturing the finished dosage form and performing release quality control) for compliance with GMP, conducted by the authorized body of the manufacturing country or the authorized body of a Member State within the last 3 years, as well as the plan and report on the implementation of corrective and preventive actions (CAPA) after the inspection (if any), and in cases stipulated by paragraph 30 of the Rules for the Registration and Examination of Medicinal Products for Human Use, a link to the authorized body's website on the Internet containing information from the GMP inspection database (e.g., EudraGMP). When submitting the documents specified in paragraph 1.6.1 of these Requirements, as well as as part of the procedure for bringing them into compliance with Union requirements, the submission of information is optional.
(paragraph 1.6.3 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
1.6.4 - 1.6.5. Repealed effective December 20, 2023. - Decision of the Council of the Eurasian Economic Commission dated October 20, 2023 No. 114.
1.6.6. Information on any regulatory measures taken by the authorized body over the past three years based on the results of inspections at the declared manufacturing site (if any). When submitting the documents specified in paragraph 1.6.1 of these Requirements, as well as as part of the procedure for bringing them into compliance with Union requirements, the submission of information is optional.
(as amended by Decision of the Council of the Eurasian Economic Commission dated October 20, 2023 No. 114)
1.6.7. A letter from the authorized person for quality on the compliance of the manufacturing conditions of the medicinal product submitted for registration with the requirements of the Rules of Good Manufacturing Practice of the Union, including with respect to starting materials for each manufacturing site used in the manufacturing of the medicinal product and active pharmaceutical ingredient, including sites where quality control and in-process control are carried out. The letter must be signed by a quality representative and certified by the manufacturer's seal (stamp), if necessary, with a Russian translation.
1.6.8. Information on complaints regarding the quality of medicinal products manufactured at the manufacturing site of the medicinal product being submitted for registration over the past three years, or confirmation of the absence of complaints. When submitting the documents specified in paragraph 1.6.1 of these Requirements, as well as as part of the procedure for bringing the product into compliance with Union requirements, the submission of information is optional.
1.6.9. Consent to conduct a pharmaceutical inspection for compliance with the requirements of international treaties and acts constituting the law of the Union.
1.6.10. Repealed effective December 20, 2023. - Decision of the Council of the Eurasian Economic Commission dated October 20, 2023 No. 114.
1.6.11. A diagram of the production stages indicating all production sites involved in the production of the medicinal product and active pharmaceutical ingredient, including final quality control.
1.7. Information on specialists:
1.7.1. Information on the specialist who prepared the quality summary (if any). Submission of information is not mandatory as part of the procedure for bringing the product into compliance with Union requirements.
(clause 1.7.1 as amended by Decision of the Council of the Eurasian Economic Commission dated October 20, 2023 No. 114)
1.7.2. Information on the specialist who prepared the preclinical study summary (if any). Submission of information is optional as part of the process for aligning with Union requirements.
(Clause 1.7.2 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
1.7.3. Information on the specialist who prepared the clinical trial summary (if any). Submission of information is optional as part of the process for aligning with Union requirements.
(As amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
Information on the quality, preclinical, and clinical data specialists includes information on their education, specialization, and professional experience. It must be signed by the specialists who prepared the summary and review of quality, preclinical, and clinical data. These specialists must have the appropriate qualifications. The existence of a professional relationship between the specialist who prepared the summary and the applicant must be indicated.
1.8. Specific requirements for different types of applications:
1.8.1. A letter from the Marketing Authorization Holder regarding an additional trade name for a medicinal product is submitted if the applicant plans to register the medicinal product under different trade names in the country of manufacture, the reference state, and the state of recognition (if applicable). The letter must include guarantees that a single registration dossier is used for these purposes. The letter must be signed and dated by the Marketing Authorization Holder. Submission of information is not mandatory as part of the procedure for aligning with Union requirements.
1.8.2. Clinical trial documents and summaries substantiating the registration application (if applicable):
(clause 1.8.2 as amended by Decision of the Council of the Eurasian Economic Commission dated 05.03.2021 No. 14)
1.8.2.1. Permission from the authorized body to conduct a clinical trial in Member States, including amendments (if any) to the clinical trial protocol. Submission of information is not mandatory as part of the procedure for bringing the clinical trial into compliance with Union requirements.
(Clause 1.8.2.1 as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated October 20, 2023)
1.8.2.2. A list of inspections conducted for compliance with the Good Clinical Practice Rules of the Eurasian Economic Union, approved by Decision No. 79 of the Council of the Eurasian Economic Commission dated November 3, 2016, for the medicinal product applied for registration, indicating the authorized bodies that conducted the inspections, the dates of the inspections, and the results (regardless of the availability of the documents specified in paragraph 1.8.2.1 of these Requirements). If necessary, the authorized bodies (expert organizations) of the member states independently request the results of these inspections from the relevant regulatory authorities. Submission of information is not mandatory as part of the procedure for bringing the medicinal product into compliance with Union requirements. (as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated October 20, 2023)
The list of inspections includes inspections of study centers that participated in clinical trials of the medicinal product, inspections of the sponsor or contract research organization for the clinical trial of the medicinal product, or inspections of other organizations related to the trial (e.g., an analytical laboratory involved in the clinical trial of the medicinal product), and other GCP inspections.
If a clinical trial was conducted entirely at study centers in third countries, the list must include the results of GCP inspections conducted at the study centers that enrolled the maximum number of patients in the trial of the medicinal product. This list also includes indications of inspections conducted for other clinical trials at the same study center (including for another medicinal product for which the applicant and/or the declared MAH are not the MAH). In this case, the authorized bodies (expert organizations) of the Member States shall independently request reports on such inspections from the relevant authorized bodies of third countries (in the absence of the documents specified in paragraph 1.8.2.1 of these Requirements (if applicable)).
(as amended by Decision of the Council of the Eurasian Economic Commission of 20.10.2023 No. 114)
1.8.2.3 - 1.8.2.4. Repealed effective 20 December 2023. - Decision of the Council of the Eurasian Economic Commission of 20.10.2023 No. 114.
1.8.2.5. Summary of the application for registration of a medicinal product with well-studied medical use. Submission of information is not mandatory as part of the procedure for bringing the product into compliance with Union requirements.
(paragraph 1.8.2.5 as amended by Decision of the Council of the Eurasian Economic Commission of 20.10.2023 No. 114)
1.8.2.6. Summary of the registration application for generic, hybrid, or biosimilar medicinal products (if applicable). Submission of information is optional during the process of harmonizing with Union requirements.
(Section 1.8.2.6 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
1.8.2.7. Summary of the registration application if patents exist in a Member State for the medicinal product being registered.
(Section 1.8.2.7 introduced by Decision of the Council of the Eurasian Economic Commission dated 05.03.2021 No. 14)
1.8.2.8. Summary of the registration application in exceptional cases (if applicable). Submission of information is optional during the process of harmonizing with Union requirements.
(Clause 1.8.2.8 as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated 20.10.2023)
1.8.2.9. Summary of the application for registration with the establishment of post-registration measures or summary of the application for conditional registration (if applicable). Submission of information is not mandatory as part of the procedure for bringing the application into compliance with Union requirements.
(Clause 1.8.2.9 as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated 20.10.2023)
1.8.3. Table listing clinical trials (if applicable). Submission of information is not mandatory as part of the procedure for aligning with Union requirements.
(Section 1.8.3 as amended by Decision of the Council of the Eurasian Economic Commission of 20.10.2023 No. 114)
1.8.4. Repealed effective 20 December 2023. - Decision of the Council of the Eurasian Economic Commission of 20.10.2023 No. 114.
1.9. Applicant's documents on the assessment of potential environmental hazards (posted as Appendix No. 1 to the module) (if any).
1.9.1. Applicant's letter stating that the medicinal products contain or are derived from genetically modified organisms (if applicable).
1.10. Information regarding the applicant's pharmacovigilance in the Member State.
1.10.1. A master file of the pharmacovigilance system of a marketing authorization holder, in accordance with the requirements of the Rules of Good Pharmacovigilance Practice of the Eurasian Economic Union, approved by the Commission (hereinafter referred to as the Rules of Good Pharmacovigilance Practice of the Union), is submitted when the marketing authorization holder first applies for registration of a medicinal product in the Union market.
(as amended by Decision of the Council of the Eurasian Economic Commission dated 30.01.2020 No. 9)
For subsequent applications for registration of medicinal products on behalf of this marketing authorization holder, a brief description of the marketing authorization holder's pharmacovigilance system is submitted.
The brief description of the marketing authorization holder's pharmacovigilance system must include, among other things, the following elements:
written confirmation by the marketing authorization holder of the existence of an authorized person responsible for pharmacovigilance. If the Marketing Authorization Holder is not located in a Member State, confirmation of the presence of a pharmacovigilance contact person in the Member State is also required;
Statement of the country in which the authorized person resides and performs their functions;
Contact details of the authorized person and the pharmacovigilance contact person (if applicable);
A statement (declaration) signed by the Marketing Authorization Holder stating their commitment to fulfill the tasks and obligations listed in the Union's Good Pharmacovigilance Practice Rules;
A link to the location (address) of the pharmacovigilance system master file.
1.10.2. Written confirmation by the Marketing Authorization Holder of the presence of a authorized person responsible for pharmacovigilance in the Member State.
1.10.3. A risk management plan for the medicinal product submitted for registration, prepared in accordance with the Union's Good Pharmacovigilance Practice Rules.
1.10.4. Duly certified documents confirming the existence of interactions that ensure the proper performance of all duties of the registration certificate holder by several legal entities, if the holders of the registration certificates for the medicinal product issued by the reference state and the states of recognition are different legal entities (if applicable).
1.11. Copies of documents confirming trademark registration (if any).
2. Requirements for the registration dossier documents
provided in Module 2: Summary of the General Technical Document (GTD)
This module provides summaries of the chemical and biological documentation, preclinical and clinical studies presented in Modules 3–5 of the medicinal product registration dossier, and the opinions of the specialists who prepared the summaries on quality, preclinical, and clinical studies.
(as amended by Decision No. 9 of the Council of the Eurasian Economic Commission dated January 30, 2020)
Summarized factual data are presented, including materials in tabular form. These reports provide cross-references to tables or information contained in the primary documentation presented in Module 3 "Quality," Module 4 "Preclinical (Non-Clinical) Study Reports," and Module 5 "Clinical Study (Trial) Reports."
Summaries and summaries must comply with the core principles and requirements set forth below.
2.1. Contents of Modules 2-5.
This section of the module presents the content of the documentation on the quality, safety, and efficacy of the medicinal product included in Modules 2-5.
2.2. Introduction to the CTD.
This document should provide information on the pharmacological group, mechanism of action, and proposed clinical use of the medicinal product.
2.3. General Quality Summary.
The General Quality Summary should provide an overview of information related to chemical, pharmaceutical, and biological data.
Specific attention should be paid to key critical parameters and issues related to quality aspects, and justification should be provided in cases where relevant requirements and guidelines are not met. This document should cover the issues and describe the relevant data detailed in Module 3. (as amended by Decision of the Council of the Eurasian Economic Commission dated January 30, 2020, No. 9)
2.4. Review of Preclinical Data.
A summary and critical assessment of the in vitro animal preclinical studies of the medicinal product must be provided, along with a discussion and justification of the study strategy where deviations from relevant requirements are necessary.
An assessment of impurities and degradation products of the medicinal product must be included, along with their potential pharmacological and toxicological effects, with the exception of medicinal products of biological origin. Any differences in the chirality, chemical form, and purity of the compounds used in preclinical studies and the medicinal product to be manufactured must be considered.
For medicinal products of herbal and biological origin, the comparability of the product used in preclinical studies, clinical trials, and the medicinal product to be registered must be assessed.
Any new excipient must be subject to a separate safety assessment.
The properties of the medicinal product demonstrated in preclinical studies must be identified, and the significance of the safety results for the planned clinical use of the medicinal product must be presented.
2.5. Clinical Data Review.
The clinical data review should contain a critical analysis of the clinical data included in the executive summary and Module 5. It should provide information on the clinical development of the medicinal product, including study design, decisions made regarding the study, and the conduct of the studies.
It should provide a brief overview of the clinical trial data, including important limiting factors, as well as a benefit-risk assessment based on the clinical trial findings. It should also justify the proposed dose and indications for use based on the obtained clinical efficacy and safety data. It should also assess how the general characteristics of the medicinal product, the instructions for medical use, and other approaches can optimize benefits and limit risks.
It is necessary to explain any unanswered questions regarding efficacy and safety that arose during the development process.
2.6. Summary of preclinical studies.
Preclinical study summaries should be presented based on the actual results of pharmacological, pharmacokinetic, and toxicological studies conducted on animals in vitro, in text format and in tables in the sequence presented below, with an introductory section.
2.6.1. Pharmacological study summaries in text format.
2.6.2. Pharmacological study summaries in tables.
2.6.3. Pharmacokinetic study summaries in text format.
(as amended by Decision No. 9 of the Council of the Eurasian Economic Commission of 30.01.2020)
2.6.4. Summary of pharmacokinetic studies in tabular form.
2.6.5. Summary of toxicological studies in text format.
2.6.6. Summary of toxicological studies in tabular form.
2.7. Summary of clinical studies.
A detailed summary of clinical information on the study of the medicinal product included in Module 5, including factual data, must be provided. The summary must include the results of all biopharmaceutical studies, clinical pharmacology studies, and clinical efficacy and safety studies. A brief overview of individual studies must be provided. The clinical information in the summary form must be presented in a specific sequence of parts (with a list of referenced scientific sources).
2.7.1. Summary of biopharmaceutical studies and associated analytical methods.
2.7.2. Summary of clinical pharmacology studies.
2.7.3. Summary of clinical efficacy.
2.7.4. Summary of clinical safety.
2.7.5. Copy of references.
2.7.6. Summary of individual studies.
3. Requirements for Registration Dossier Documents
listed in Module 3: Quality
3.1. Contents of Module 3.
3.2. Key information required for submission includes:
а) Chemical, pharmaceutical, and biological data on the active pharmaceutical ingredients and the medicinal product, including information on the development, manufacturing process, characteristics and properties, quality control methods and requirements, stability, as well as a description of the composition and packaging of the medicinal product;
b) Basic information on the active pharmaceutical ingredient and the medicinal product;
c) Detailed information on the starting materials and raw materials used in the production of the active pharmaceutical ingredient and excipients included in the medicinal product;
d) All test methods and techniques used in the production and quality control of the active pharmaceutical ingredient and the medicinal product, clearly and in detail, so that they can be reproduced during control testing at the request of the authorized body of the reference state. All test methods must comply with the current scientific level and be validated. The results of the validation of the methods must be provided. When using test methods included in the Eurasian Economic Union Pharmacopoeia, the pharmacopoeias of the member states, and the primary pharmacopoeias, in accordance with the Concept for Harmonization of Pharmacopoeias of the Eurasian Economic Union Member States (hereinafter referred to as the Concept), the corresponding references to the monographs and general sections must be provided;
e) For all pharmaceutical substances specified in the monographs of the Eurasian Economic Union Pharmacopoeia, the pharmacopoeias of the member states, and the primary pharmacopoeias in accordance with the Concept, references to the listed pharmacopoeias must be provided.
However, if a pharmaceutical substance specified in the Eurasian Economic Union Pharmacopoeia, the pharmacopoeias of the member states, and the primary pharmacopoeias in accordance with the Concept is obtained by a process that may generate impurities not controlled by the monographs of the aforementioned pharmacopoeias, then these impurities and their permissible levels must be specified, and a methodology for their determination must be provided. If the specification included in the monograph of the Eurasian Economic Union Pharmacopoeia, the pharmacopoeias of the member states, and the primary pharmacopoeias in accordance with the Concept is insufficient to ensure the quality of the substance, a more detailed specification from the manufacturer or marketing authorization holder may be required.
If analytical methods and procedures are included in the Eurasian Economic Union Pharmacopoeia, there is no need to provide them in full; a relevant reference to the monographs and general sections is sufficient;
f) if the starting materials and raw materials, active pharmaceutical ingredients, or excipients are not described in the Eurasian Economic Union Pharmacopoeia, the pharmacopoeias of the member states, and the primary pharmacopoeias in accordance with the Concept, a reference to the monograph of the pharmacopoeia of another state may be applicable. In such cases, the applicant must submit a copy of the monograph along with the validation of the analytical methods described in the monograph, as well as a translation (if necessary);
g) If the active pharmaceutical substance and/or excipient and starting material are described in a monograph of the European Pharmacopoeia, the applicant may submit a certificate of conformity with the monograph of the European Pharmacopoeia in the relevant section of this module. It is recognized that certificates of conformity with the monograph of the European Pharmacopoeia replace the essential data in the relevant sections specified in this module. If the active pharmaceutical substance has a valid marketing authorization or is included in the relevant state register in accordance with the requirements of the legislation of a Member State, the applicant has the right to replace the essential data in the relevant sections specified in this module during registration and/or when bringing the registration dossier into compliance with the Union requirements for circulation only within the territory of that Member State. The manufacturer of the active pharmaceutical substance must confirm in writing to the applicant that the manufacturing process has not changed since the date of issue of the certificate of conformity with the monograph of the European Pharmacopoeia or inclusion in the relevant register of the Member State;
(subparagraph "g" as amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated March 17, 2022)
h) For well-studied (at least 10 years from the date of the first systematic and documented use of the active ingredients of the medicinal product, in at least three Member States, with the exception of biological ones) active pharmaceutical ingredients, the manufacturer of the active pharmaceutical ingredient or the applicant for registration of the medicinal product may prepare a separate document including the following information (active pharmaceutical ingredient dossier or master file):
a detailed description of the manufacturing process;
quality control during manufacturing;
a manufacturing process validation report.
The manufacturer of the active pharmaceutical ingredient may submit the master file for the active pharmaceutical ingredient to the authorized body of the Member State. When using an active pharmaceutical ingredient master file as part of a medicinal product registration dossier, the manufacturer of such active pharmaceutical ingredient must provide the applicant (registration certificate holder) of the relevant medicinal product with all necessary data to bear the liability stipulated by these Rules. The manufacturer of the active pharmaceutical ingredient must provide the applicant (registration certificate holder) with written confirmation guaranteeing the consistency of batch quality and that no changes will be made to the manufacturing process or specifications of such active pharmaceutical ingredient without notifying the applicant (registration certificate holder). The documents and data required to make such a change must be submitted to the authorized body; these documents and data are also submitted to the applicant for the sections pertaining to the open portion of the active pharmaceutical ingredient master file.
If the applicant does not have complete information regarding the restricted portion of the active pharmaceutical ingredient master file from which it is manufactured due to confidentiality, a written consent from the manufacturer of the active pharmaceutical ingredient must be attached to the application, provided that information about it is included in the unified register. This consent must grant the authorized body the right to use previously submitted information from the restricted portion of the master file for the specified active pharmaceutical ingredient during the expert evaluation of the medicinal product;
i) Special measures to prevent the transmission of animal spongiform encephalopathies (raw materials obtained from ruminants) must be described: at each stage of the manufacturing process, the applicant must confirm the compliance of the materials used with the requirements of the guidelines for minimizing the risk of transmission of animal spongiform encephalopathies according to the Pharmacopoeia of the Eurasian Economic Union or provide a certificate of conformity with a specific monograph of the European Pharmacopoeia or scientific data to substantiate this conformity;
j) Information on the risk assessment of potential contamination by extraneous agents (viral or non-viral) should be provided in accordance with the requirements set out in specific guidelines, as well as in the general articles (monographs) and general sections of the Pharmacopoeia of the Eurasian Economic Union, the pharmacopoeias of the Member States, and the main pharmacopoeias in accordance with the Concept;
k) Special devices and equipment used at any stage of the manufacturing process and the control stage of the medicinal product must be described in detail;
l) If necessary, documents confirming the registration of the medical device in accordance with the rules approved by the Commission must be provided.
3.2.S. Active pharmaceutical substance.
3.2.S.1. General information on starting materials and raw materials:
a) the name of the active pharmaceutical ingredient, including the recommended international nonproprietary name (INN), and, if available, the pharmacopoeial name according to the Pharmacopoeia of the Eurasian Economic Union, and the chemical name according to IUPAC nomenclature.
The structural formula, including the relative and absolute spatial structure, the molecular (empirical) formula, and the relative molecular weight, are provided. For biotechnologically derived medicinal products, if applicable, a schematic amino acid sequence and relative molecular weight must be provided.
For biological medicinal products, a list of the physicochemical and other important properties of the active pharmaceutical ingredient, including its biological activity, must be provided;
b) for the purposes of this section, starting materials are considered to be all materials from which active pharmaceutical ingredients are manufactured or isolated. For medicinal products of biological origin, starting materials are considered to be any materials of biological origin (e.g. microorganisms, organs and tissues of plant or animal origin, cells or fluids (including blood or plasma) of humans or animals, biotechnological cellular components (recombinant or non-recombinant cell substrates, including primary cells)).
A medicinal product of biological origin (for the purposes of this paragraph) is considered to be all medicinal products whose active ingredient (hereinafter referred to as the active ingredient) is a biological substance (material).
A biological substance is a substance obtained from a biological source, the description and quality confirmation of which requires the submission of a combination of physical, chemical, and biological analytical methods, along with a description of the manufacturing process and its controls.
Any other substances used for the production or isolation of an active substance or active component, but from which this active substance or active component is not directly obtained (namely, reagents, culture media, fetal or embryonic serum, additives and buffers used in preparative chromatography, etc.), are considered raw materials.
3.2.S.2. Active Pharmaceutical Ingredient Manufacturing Process:
a) The applicant is obliged to provide a description of the manufacturing process for the active pharmaceutical ingredient. To adequately describe the manufacturing process and its controls, the necessary information must be presented in accordance with the requirements established in the relevant acts within the Union law;
b) All starting materials and supplies required for the production of the active pharmaceutical ingredient must be listed, indicating the production stage at which each type of raw material and supplies is used. Information on their quality and control, as well as information confirming compliance with the requirements (standards) for the intended use, must be provided. The starting materials (raw materials) must be listed, along with quality and quality control documentation. The name and location of the production sites must be provided, and the responsibilities of each manufacturer, including contract manufacturing, must be specified, as well as information on each production site or testing laboratory used; (as amended by Decision of the Council of the Eurasian Economic Commission dated 30.01.2020 N 9)
c) The following additional requirements are established for biological medicinal products:
A description and documentary evidence of the origin and history of the source materials must be provided;
Regarding special measures to prevent the transmission of pathogens causing spongiform encephalopathy, the applicant must confirm that the active substance meets, in particular, the requirements of the relevant monograph (article) of the Eurasian Economic Union Pharmacopoeia for minimizing the risk of transmission of these pathogens with manufactured medicinal products;
When using cell banks, evidence must be provided that the cell characteristics have remained unchanged over the number of passages used for production, as well as during the subsequent period;
Seed materials, cell banks, serum or plasma pools, and other materials of biological origin, as well as, if possible, the materials from which they are obtained, are tested for the presence of adventitious agents;
If the presence of potentially pathogenic adventitious agents cannot be avoided, the materials may be used only if subsequent processing ensures the removal and/or inactivation of these adventitious agents, and this must be validated;
Vaccine production must be based (where possible) on a seed culture system and known cell banks. When producing bacterial and viral vaccines, the characteristics of the infectious agent must be demonstrated using inoculum. Furthermore, for live vaccines, the stability of attenuation characteristics (reduced virulence of pathogenic microorganisms) must be confirmed using inoculum. If this evidence is insufficient, the attenuation characteristics must also be confirmed at the production stage.
For medicinal products obtained from human blood or plasma, in accordance with the provisions set out in Part III of this Appendix, the origin, criteria and methods for selection, transport and storage of starting materials must be described and documented;
The manufacturing facilities and equipment must be described;
d) Where applicable, information on testing and acceptance criteria at each critical stage, information on the quality and control of intermediate products, as well as on process validation and/or assessment must be provided;
e) If the presence of potentially pathogenic adventitious agents cannot be avoided, the materials may be used only in cases where subsequent processing ensures their removal and/or inactivation, which is confirmed by validation and is provided in the relevant section on the viral safety assessment;
f) It is necessary to provide for the active pharmaceutical ingredient a description and analysis of significant changes made to the manufacturing process during development and/or at the manufacturing site, and (if the manufacturer of the medicinal product is not the manufacturer of the active pharmaceutical ingredient) to provide a copy of the written commitment of the manufacturer of the active pharmaceutical ingredient to inform the applicant of changes in the manufacturing process or specifications (in any form).
3.2.S.3. Description of the characteristics of the active pharmaceutical ingredient:
It is necessary to provide data on the structure and other characteristics of the active pharmaceutical ingredient;
The structure of the active pharmaceutical ingredient should be confirmed based on modern physicochemical and/or immunochemical and/or biological methods, and information on impurities should be provided.
3.2.S.4. Quality control of the active pharmaceutical ingredient:
It is necessary to provide detailed information on the specifications used for batch-by-batch control of the active pharmaceutical ingredient, the rationale for the selection of these specifications, test methods, and their validation; It is necessary to present the results of quality control of individual batches produced during the development stage.
3.2.S.5. Reference Standards or Materials:
Reference materials and reference standards must be identified and described in detail. Where possible, suitable pharmacopoeial chemical reference standards and biological reference materials must be used.
3.2.S.6. Packaging (Closure) System:
A description of the primary packaging and packaging (closure) system and specifications of its components must be provided.
3.2.S.7. Stability:
a) A summary of the studies performed, the plans (programs) used, and the results obtained during the studies must be provided;
b) Detailed stability study results, presented in an appropriate format, including information on the analytical methods used and their validation, must be provided;
c) A post-marketing stability study plan (program) and the applicant's obligations for its implementation must be provided.
3.2.P. Medicinal Product.
3.2.P.1. Description and Composition of the Medicinal Product.
A description of the medicinal product and its composition must be provided. The information must include a description of the dosage form and composition, listing all components of the finished medicinal product, their quantities per unit dose, and the functional purpose of the components:
active pharmaceutical ingredient;
excipients, regardless of their origin or quantity, including colorants, preservatives, modifiers, stabilizers, thickeners, emulsifiers, flavorings, and aromatic substances, etc.;
components of the dosage form and outer shells of medicinal products ingested by the patient or by any other route of administration (hard capsules, soft capsules, rectal capsules, film-coated tablets, film-coated tablets, etc.).
This information must be supplemented with any relevant data regarding the type of container and its closure method (if applicable), along with detailed information about the devices through which the medicinal product will be used or administered and which will be supplied with the medicinal product. The term "accepted terminology" used to describe the components of medicinal products, regardless of other provisions, means the following:
for substances with an INN recommended by the World Health Organization (WHO), the INN, or if the substance is in salt, ester, hydrate, or other form, the corresponding modified INN;
for other substances (in the absence of an INN), the generally accepted (group) name, taking into account salt, ester, hydrate, and other forms; in the absence of a generally accepted (group) name, the chemical name according to the IUPAC nomenclature; and, in the absence of the latter, information on sources and methods of production, the presence of added additives, etc. (with relevant detailed information, if necessary);
for colorants, in addition to the name, the corresponding code according to the International Food Additive Numbering System (Codex Alimentarius) (E-codes) is provided.
In the "Quantitative Composition" section of the medicinal product, for the active pharmaceutical ingredient, it is necessary to indicate, depending on the dosage form, the mass or number of biological activity units per dosage unit of the dosage form, or per unit mass, or per unit volume of each active pharmaceutical ingredient.
If the active pharmaceutical ingredients are presented as compounds or derivatives, their quantitative expression must be provided, indicating their total mass and the mass of the active moiety (if applicable).
For medicinal products containing an active pharmaceutical ingredient that is first declared in the composition of a medicinal product, the quantity of the active pharmaceutical ingredient that is a salt or hydrate must always be indicated based on the mass of the active moiety.
For medicinal products containing an active pharmaceutical ingredient that is first registered in a medicinal product in a Member State, the quantitative content of such an active pharmaceutical ingredient, if it is a salt or hydrate, must be expressed according to the systems approach based on the mass of the active moiety. The quantitative content of the same active pharmaceutical ingredient in all subsequent medicinal products registered in Member States must be indicated in the same manner.
For a substance or active substance that cannot be determined chemically, units of biological activity or, if available, international units of biological activity established by the World Health Organization (WHO) must be indicated. If international units have not been established by the WHO, units of biological activity must be expressed in a manner that provides accurate information on the activity of the substance or active substance, using, where appropriate, units of the Pharmacopoeia of the Eurasian Economic Union (EAEU). Where possible, biological activity per unit mass should be indicated.
3.2.P.2. Pharmaceutical Development:
This section contains information on development studies conducted to demonstrate that the dosage form, composition, manufacturing process, packaging (closure) system, microbiological characteristics, and instructions for preparing the final dosage form suitable for immediate use are consistent with the intended use indicated by the applicant in the medicinal product registration dossier. The studies described in this section differ from routine control testing conducted according to specifications. Critical formulation parameters and process characteristics that may impact batch reproducibility, performance, and quality of the medicinal product must be identified and described. When presenting additional supporting data, reference should be made to the relevant sections of Modules 4 and 5:
It is necessary to justify the compatibility of the active pharmaceutical substance with excipients, as well as the main physicochemical properties of the active pharmaceutical substance that may affect the characteristics of the medicinal product, or the compatibility of different active pharmaceutical substances with each other in the case of combination medicinal products;
It is necessary to justify the choice of excipients, especially with regard to their respective functional characteristics and content;
It is necessary to provide a description of the development of the medicinal product, taking into account the proposed route of administration and route of use;
The presence of any excess in the composition must be justified;
It is necessary to identify and justify any physicochemical and biological properties and any parameters affecting the characteristics of the medicinal product;
It is necessary to provide information on the selection and optimization of the manufacturing process, as well as on the differences (discrepancies) between the manufacturing process used to manufacture the batches involved in the clinical trial phases and the planned industrial process for the production of the finished medicinal product;
It is necessary to justify the suitability of the primary packaging and the closure system used for storage, transportation, and use of the medicinal product. A description of the potential interaction between the medicinal product and the primary packaging material may be required;
For both non-sterile and sterile medicinal products, the microbiological characteristics of the dosage form must be provided in accordance with the requirements of the Eurasian Economic Union Pharmacopoeia;
To provide relevant additional information on the use of solvents or a dispenser (dispensing device), the compatibility of the medicinal product with the solvents intended for dilution before use or with the dispenser must be substantiated.
3.2.P.3. Medicinal Product Manufacturing Process:
a) A description of the manufacturing method specified in the medicinal product registration application shall be presented in such a way as to provide an adequate summary of the nature of the operations performed.
To this end, the description of the manufacturing method shall include, at a minimum:
a description of the various stages of production, including in-process controls and relevant acceptance criteria to assess whether the processes used in manufacturing may result in any undesirable changes in the components of the dosage form;
a description of the measures necessary to ensure the homogeneity of the medicinal product (in the case of a continuous manufacturing process);
Results of experimental studies to validate the manufacturing process using non-standard manufacturing methods or if the process is critical to the medicinal product;
A description of existing sterilization processes and/or procedures for ensuring aseptic conditions (for sterile medicinal products);
A detailed manufacturing recipe (batch composition).
The name and location of the manufacturing sites and the responsibilities of each manufacturer, including contract manufacturing, must be provided, as well as information on each manufacturing site or testing laboratory used;
b) A description of the analytical methods for quality control of the medicinal product that can be used at intermediate stages of the manufacturing process must be provided to ensure the uniformity of the manufacturing process.
These methods are important for verifying the conformity of the medicinal product with the manufacturing formula, especially in cases where the applicant proposes an analytical method for monitoring the medicinal product that does not include the quantitative determination of all active pharmaceutical ingredients (or all excipients that must meet the same requirements as active pharmaceutical ingredients).
This also applies to cases where the quality control of the medicinal product depends on in-process testing, especially in cases where the method of manufacturing the medicinal product significantly affects its quality;
c) A description, documentation, and results of validation studies for critical production points or quantitative determination methods used in the manufacturing process must be provided.
3.2.P.4. Quality Control of Excipients:
a) A list of all starting materials used for the production of excipients must be provided, indicating at which stage of the process each of them is used. Information on the quality and quality control of these starting materials must be provided, as well as information demonstrating that the materials meet standards for their intended use.
In all cases, colorants must meet the requirements of the relevant article (monograph) of the Pharmacopoeia of the Eurasian Economic Union and the requirements of the Technical Regulation of the Customs Union "Safety Requirements for Food Additives, Flavorings, and Processing Aids" (TR CU 029/2012), adopted by Decision No. 58 of the Council of the Commission dated July 20, 2012. In addition, colorants must meet the purity criteria established by the requirements of acts constituting the Union's law;
b) Specifications and their justification must be provided for each excipient. The analytical methods used to control their quality must be described and properly validated;
c) Particular attention must be paid to excipients of human or animal origin. To comply with special measures to prevent the transmission of animal spongiform encephalopathy pathogens, the applicant must also confirm for excipients that the medicinal product meets, in particular, the requirements of the relevant monograph of the Eurasian Economic Union Pharmacopoeia for minimizing the risk of transmission of these pathogens with manufactured medicinal products.
Compliance with the above requirements can be confirmed by submitting a certificate of conformity with the European Pharmacopoeia monograph on the pathogens of animal spongiform encephalopathy or other documents (data) substantiating this conformity;
d) New excipients:
For excipients used for the first time in a medicinal product or used with a new route of administration, a full description of the manufacturing, properties, and control procedures must be provided, with reference to confirmed preclinical and clinical safety data. This information must be presented in the same manner as specified above for the active pharmaceutical ingredient.
Detailed chemical, pharmaceutical, and biological information must be provided. This information must be formatted as specified in Module 3 for the active pharmaceutical ingredient.
Information on a new excipient may be submitted as a separate document compiled according to the format described above.
If the applicant and the manufacturer of the new excipient are not the same person, such a separate document must be submitted by the manufacturer to the applicant.
Additional information on the toxicity study results for the new excipient must be provided in Module 4 of the registration dossier.
Clinical trial results for the new excipient should be described in Module 5 of the medicinal product registration dossier.
3.2.P.5. Medicinal Product Quality Control. For the purposes of drug quality control, a drug batch is defined as a product comprising the entire quantity of units of the drug manufactured from the same quantity of starting materials and supplies and subjected to the same manufacturing and/or sterilization operations, or a product comprising, in a continuous manufacturing process, all units of the drug manufactured within a specified time period and characterized by homogeneity.
The maximum permissible deviation in the active pharmaceutical ingredient content of a drug on the date of manufacture must not exceed 5%, except in duly justified cases.
Detailed specification information (at the time of release of the drug and throughout its shelf life (expiration date) based on stability testing) must be provided, along with a justification for the selection of quality indicators, test methods, and the validation of these methods.
3.2.P.6. Standard Samples and Materials.
Standard materials and reference standards used for quality control of the medicinal product must be identified and described in detail, unless information on them is already included in the section of the registration dossier containing documents and data on the active pharmaceutical ingredient.
3.2.P.7. Packaging (Closure) System.
A description of the primary (inner) packaging and closure system must be provided, including the materials from which each component of the primary packaging is made, as well as the specifications for these materials. Specifications must include a description and identification of the materials. Information on non-pharmacopeial analytical methods (including method validation) must be provided, if applicable.
For non-functional materials of secondary (consumer) and intermediate packaging, only a brief description is provided. For functional components of secondary (consumer) and intermediate packaging, additional information is provided.
3.2.P.8. Drug Product Stability:
a) A summary of the types of studies performed, the plans (programs) used, and the results obtained during the studies must be provided;
b) Detailed stability study results, recorded in an appropriate format, must be provided, including information on the analytical procedures used and the validation of the analytical procedures.
For vaccines, information on cumulative stability must be provided, if applicable.
c) A post-registration stability study plan (program) and the applicant's obligations to implement this plan must be submitted.
3.2.A. Additions.
3.2.A.1. Manufacturing facilities and equipment.
3.2.A.2. Safety assessment of medicinal products with respect to the presence of extraneous agents.
3.2.A.3. New excipients.
3.2.R.1. Excluded. - Decision of the Council of the Eurasian Economic Commission dated March 17, 2022, No. 36.
3.2.R.2. Manufacturing process validation plan.
A manufacturing process validation plan (for traditional validation) or a continuous verification plan for the manufacturing process (for an extended approach to manufacturing process validation) must be submitted. (clause 3.2.R.2 as amended by Decision of the Council of the Eurasian Economic Commission dated March 17, 2022 No. 36)
3.2.R.3 - 3.2.R.5. Excluded. - Decision of the Council of the Eurasian Economic Commission dated March 17, 2022 No. 36.
4. Requirements for the registration dossier documents provided
in Module 4: Preclinical (Non-clinical) Study Reports
4.1. Contents of Module 4.
4.2. Preclinical (Non-clinical) Study Reports.
In certain cases, in accordance with the requirements for studying individual groups of drugs in Part II of these Requirements and the Rules for Registration and Evaluation of Medicinal Products for Human Use approved by the Commission, this section may provide a review of scientific literature data instead of the results of the Commission's own preclinical studies.
Documents in the registration dossier on pharmacological and toxicological testing must define:
the potential toxicity of the medicinal product and any harmful or undesirable toxic reactions that may be observed under the proposed conditions of its use in humans, with an assessment of these reactions taking into account the relevant pathological conditions;
the pharmacological properties of the medicinal product in terms of qualitative and quantitative indicators and in accordance with the stated clinical use. All results must be reliable and generally applicable. When planning experimental studies and evaluating the obtained data, mathematical and statistical methods of data processing must be used.
Furthermore, the registration dossier must provide information for healthcare professionals on the therapeutic and toxicological potential of the medicinal product. For biological medicinal products such as immunological medicinal products and medicinal products derived from human blood and plasma, the requirements of this module of the medicinal product registration dossier may need to be adapted to the specific medicinal product. Therefore, the applicant must provide a justification for the study program used.
The medicinal product registration dossier, with respect to its study program, must stipulate that:
all studies requiring multiple administrations of the medicinal product are planned taking into account the possible stimulation of antibody formation and the effect of antibodies on the body;
the feasibility of conducting studies of reproductive function, embryonic (fetal) and perinatal toxicity, as well as the possible mutagenic and carcinogenic effects of the medicinal product, are analyzed. If the cause of toxicity is not the active substance (in the description of Module 4 and Module 5, the terms "active (active) substance," "active substance," and "active substance" are analogous), but other substances, then the studies may be omitted, provided that the validation results confirm that these components have been removed from the medicinal product. If an excipient is being used in pharmaceutical practice for the first time, toxicological and pharmacokinetic studies must be conducted.
If there is a risk of significant degradation of the drug during storage, toxicological studies of the degradation products must be considered.
4.2.1. Pharmacology.
In a medicinal product registration dossier, two different aspects of pharmacological studies must be covered:
the pharmacodynamic activity of the medicinal product proposed for therapeutic use must be adequately studied and described. Where possible, recognized and validated study methods (both in vivo and in vitro) must be used. New experimental methods must be described in sufficient detail to ensure their reproducibility. Results must be presented as quantitative indicators (e.g., dose-response and/or time-response curves, etc.). The results must be compared with data characterizing a substance or substances with a similar therapeutic effect. The absence of comparative studies must be justified;
the applicant must study the potential adverse pharmacodynamic effects of the substance in relation to changes in physiological functions in a living organism. Such studies must be conducted at exposures within and beyond the expected therapeutic dose range. If experimental methods are not standard, they must be described in sufficient detail and validated (to ensure their reproducibility and confirm their reliability). Any quantitative changes in the responses to repeated administration of the active substance must be investigated.
Registration dossier documents for studying the pharmacodynamic interactions of fixed-dose combinations of active substances must be based on the pharmacological justification or indications for use of these fixed-dose combinations. In the former case, the pharmacodynamic study must confirm the interactions that make such a combination significant for therapeutic use. In the latter case, when the scientific justification for such a combination of substances is based on experimental therapy, the study establishes the feasibility of confirming in animals the pharmacological action expected from such a combination of active substances in humans and at least the significance of any identified adverse effects. (as amended by Decision of the Council of the Eurasian Economic Commission dated January 30, 2020, No. 9)
4.2.2. Pharmacokinetics.
Pharmacokinetic study documents for a registration dossier include the results of analysis of all processes occurring with the active substance and its metabolites in vivo, and cover the absorption, distribution, biotransformation, and elimination of the active substance and its metabolites.
The study of each stage (absorption, distribution, biotransformation, and elimination) can be performed using physical, chemical, or biological methods, as well as by studying the actual pharmacodynamic activity of the active substance itself.
Information on the distribution and elimination of the active substance from the body is necessary in all cases where data on the distribution and elimination of the active substance are essential for determining the dosage of a medicinal product for humans, as well as for chemotherapeutic agents (antibiotics, etc.) and substances whose use depends on their non-pharmacodynamic effects (e.g., diagnostic drugs, etc.).
In vitro studies are more appropriately conducted using test systems derived from humans than using test systems of animal origin (e.g., studies of active substance binding to proteins, metabolism, and drug interactions).
The registration dossier of a medicinal product must include the results of pharmacokinetic studies of the pharmacologically active substances. When using new fixed-dose combinations of known active substances that have already been studied in accordance with the provisions of acts on the circulation of medicines within the Union, information on the applicant's own pharmacokinetic studies may be omitted from the registration dossier if such a decision is justified by the results of toxicity studies and experimental therapeutic trials. The pharmacokinetic study program should ensure comparison of pharmacokinetic data obtained in animals and humans and extrapolation of the pharmacokinetic results obtained in animals to humans.
4.2.3. Toxicology.
4.2.3.1. Toxicity of the active substance of the medicinal product after a single administration.
Documents in the medicinal product registration dossier for single-dose toxicity studies include a qualitative and quantitative analysis of toxic manifestations that may arise following a single administration of the active substance or substances contained in the medicinal product in the same proportions and in the same physicochemical state as in the finished medicinal product.
Single-dose toxicity studies must be conducted in accordance with Commission guidelines or, in their absence, the relevant guidelines of Member States.
4.2.3.2. Toxicity after repeated (multiple) administration.
Documentation of the registration dossier for repeated (multiple) administration toxicity studies should reflect the identification of any physiological and/or pathological changes that have arisen as a result of multiple administration of the active substance or combination of active substances, and a determination of how these changes are dose-dependent.
The registration dossier should preferably include information obtained from two studies: a short-term study (lasting 2-4 weeks) and a long-term study.
The duration of the long-term study depends on the duration of clinical use of the medicinal product.
Its objectives are to experimentally identify and characterize potential adverse events that should be considered during clinical trials.
The duration of repeated dose toxicity tests should comply with Commission guidelines, or, in their absence, with relevant Member State guidelines.
4.2.3.3. Genotoxicity.
The registration dossier for a medicinal product should include information on the mutagenic and clastogenic potential of the medicinal product. This information is intended to identify any disturbances that the active substance may cause in the genetic material of an individual organism or in cells. Mutagenic substances pose a risk to human health because their action causes mutations in germ cells and the development of hereditary disorders, as well as mutations in somatic cells, which can lead to the development of malignancies. These studies are mandatory for all new active substances.
4.2.3.4. Carcinogenicity.
The registration dossier of a medicinal product contains information on studies of its carcinogenic potential, which are typically conducted in the following cases:
the medicinal product is intended for long-term, continuous or intermittent use throughout the patient's life;
multiple-dose toxicity studies of the medicinal product revealed changes with suspected carcinogenic potential in test systems;
the active substance belongs to a chemical class or is structurally similar to known carcinogens or co-carcinogens (if the medicinal product belongs to the same pharmacological (chemical) class of compounds or has a similar structure, or if the conclusion is based on data from a repeated-dose toxicity study).
There is no need to conduct studies on the carcinogenic potential of clearly genotoxic compounds, as these compounds are carcinogens that pose a risk to humans. If such a medicinal product is intended for long-term treatment of patients, a long-term study may be necessary to detect early oncogenic effects.
4.2.3.5. Reproductive and developmental toxicity.
The drug's registration dossier includes information on studies of possible reproductive dysfunction in males and females, as well as adverse effects on offspring.
These studies are conducted using appropriate trials, which include studies of the medicinal product's effect on reproductive function in sexually mature male and female animals, studies of toxic and teratogenic effects on offspring at all stages of development from conception to sexual maturity, and studies of latent effects when the study medicinal product was administered to pregnant female animals.
The absence of such studies in the drug's registration dossier must be adequately justified.
Depending on the indications for use of the drug, additional studies (e.g., studies of the effects on the development of offspring) may be required when administration of the drug to immature animals is justified.
Preclinical study documents must contain information on embryofetal toxicity studies, which are typically conducted in two mammalian species, one of which must be non-rodents. Perinatal and postnatal toxicity studies must be conducted in at least one animal species.
If the metabolism of the active substance in a particular animal species is known to be similar to that in humans, it is advisable to use that species in the studies.
It is also desirable that one of the animal species be the same one used in the repeated-dose toxicity studies.
The state of scientific knowledge at the time of application should be taken into account when determining the study design. (as amended by Decision No. 9 of the Council of the Eurasian Economic Commission dated January 30, 2020)
4.2.3.6. Local Tolerability.
Preclinical study documents must contain information on local tolerability. This information reflects the study and determination of the local effect of the medicinal product (active ingredients and excipients) on body tissues in areas that may come into contact with the medicinal product during its administration during clinical use.
The study strategy must be aimed at distinguishing any mechanical effects of administration or effects due to the physicochemical properties of the medicinal product from toxic or pharmacodynamic effects.
The registration dossier of the medicinal product must demonstrate that the local tolerability study was conducted using a medicinal product developed for human use. As part of this study, animals in the control group are administered a vehicle (solvent) for administration of the study medicinal product and/or excipients. If necessary, information on the additional inclusion of a positive control group or comparator should be provided.
The design of the local tolerability study (choice of animal species, duration, frequency, route of administration, and dose) depends on the objectives of the study and the anticipated clinical use of the drug. Information on local injury reversibility studies should be provided, if necessary.
Information on animal studies may be replaced by data obtained using validated in vitro methods if the study results are of comparable quality and suitable for the safety analysis.
The sensitizing potential of chemicals applied topically (e.g., dermal, rectal, vaginal) should be assessed using at least one test system (guinea pig or local lymph node assay).
5. Requirements for Registration Dossier Documents
in Module 5: Clinical Trial Reports
5.1. Contents of Module 5.
5.2. List of all clinical studies (trials) in tabular form.
Particular attention must be paid to the presence of the following information in the registration dossier:
a) clinical information that must enable the formation of sufficiently substantiated and scientifically reliable conclusions regarding whether the medicinal product satisfies the conditions for registration. The results of all clinical trials (both favorable and unfavorable (negative) results) must be submitted;
b) clinical trials must always be preceded by appropriate pharmacological and toxicological studies (conducted in animals), information on which is provided in Module 4 of the registration dossier. The investigator must be familiar with the conclusions drawn from the pharmacological and toxicological studies. To this end, the applicant must provide them with at least an investigator's brochure containing all relevant information known at the start date of clinical trials (including chemical, pharmacological, and biological data, results of toxicological, pharmacokinetic, and pharmacodynamic studies in animals, as well as results of previous clinical trials providing adequate data necessary to justify the nature, scope, and duration of the planned study). Full reports of pharmacological and toxicological studies must be provided upon request. When using materials obtained from humans or animals, all measures to ensure safety against the possible transmission of infectious agents must be taken before the start of the study.
c) The marketing authorization holder must ensure that the key clinical trial documentation (including individual case report forms) is retained by the owners of the obtained results (except for the medical records of inpatients (outpatients)):
for 15 years from the date of completion or termination of the study;
for 2 years from the date of the last registration in Member States, provided that there are no pending or ongoing registration applications in the Union;
for 2 years from the date of formal termination of the clinical development of the investigational medicinal product.
Medical records of inpatients (outpatients) must be kept under appropriate conditions for the period provided for by the legislation of the Member State, in accordance with the maximum period permitted by the clinical center, institute, or private practice.
Documents may be retained for a longer period if required by relevant regulations or by agreement with the trial sponsor.
The trial sponsor is obligated to notify the clinical center, institute, or private practice if further document retention is no longer necessary.
The trial sponsor or other owner (holder) of the data must retain all other documentation related to the trial for the entire period during which the medicinal product has marketing authorization.
This documentation includes:
the protocol containing the rationale, objectives, statistical plan, and methodology of the trial, including the conditions under which it was conducted, the organization (management) of the trial, detailed information about the trial medicinal product, and the standard (comparator and/or placebo) used;
standard operating procedures;
all written feedback on the protocol and procedures, the investigator's brochure, and the individual case report form for each trial subject;
the final report;
the audit certificate (if any).
The final report must be kept by the trial sponsor or its legal successor for 5 years from the expiration date of the registration certificate for the medicinal product. The registration certificate holder must take additional measures to archive documentation in accordance with the Good Clinical Practice rules of the Eurasian Economic Union approved by the Commission and to implement detailed guidelines (recommendations).
Information about changes in the ownership of existing data must be formally documented, and data and documents must be submitted promptly upon request to the relevant authorized bodies.
d) The description of each clinical trial must contain sufficient information necessary to draw an objective conclusion:
a protocol containing the rationale, objectives, statistical plan, and methodology of the study, including the conditions of its conduct and organization, and detailed information about the medicinal product being studied;
an audit certificate (if any);
a list of investigators (each investigator must provide their name, address, position, qualifications, and responsibilities during the clinical trial);
location of the clinical trial;
Information on each individual patient, including case report forms;
a final report signed by the investigator, and in the case of a multicenter study, by all investigators or the coordinator (principal investigator);
e) The clinical trial data listed in subparagraphs "a" through "d" of this paragraph must be submitted to the authorized bodies responsible for drug registration. By agreement with the authorized bodies, the applicant has the right not to submit some of the listed information. Complete documentation must be provided promptly upon request of the authorized body.
The clinical trial report must reflect the investigator's opinion, based on experimental evidence, on the safety of the drug under normal conditions of use, the tolerability and efficacy of the drug, information regarding indications for use and contraindications, dosage regimen, duration of therapy, as well as special precautions to be taken during treatment and in the event of clinical symptoms of overdose. (as amended by Decision No. 9 of the Council of the Eurasian Economic Commission dated 30.01.2020)
In the report on the results of a multicenter study, the coordinating investigator must state the conclusion on the safety and efficacy of the study medicinal product on behalf of all centers during the multicenter study;
f) clinical observations for each type of study must be summarized and include the following data:
the number and gender of subjects who received the drugs;
the selection and age distribution of patients in the study and control groups;
the number of patients who withdrew from the study early and the reasons for this;
information on the outcomes of control group participants if controlled studies were conducted under the above conditions (received no treatment, received placebo, received another medicinal product with a known effect, received another type of treatment without the use of medicinal products);
the frequency of observed adverse reactions;
information about patients belonging to high-risk groups (for example, the elderly, children, pregnant women or women of reproductive age, or patients whose physiological or pathological condition requires special attention);
Parameters or criteria for evaluating efficacy and the results obtained;
statistical evaluation of the results, if required by the study design, and various influencing factors;
g) the registration dossier must include information on the investigator's observations regarding:
any signs of tolerance, dependence, or difficulties experienced by patients upon discontinuation of the medicinal product;
any interactions that occurred during concomitant administration with other medicinal products;
criteria determining the need to exclude certain patients from the study;
fatalities during the study or during the follow-up period;
h) information on the new combination of active substances must be identical to the data on the new medicinal product; the registration dossier must include a justification for the safety and efficacy of the combination;
i) if the registration dossier of the medicinal product is completely or partially missing the data listed in subparagraphs "a" - "h" of this paragraph, an explanation of the reason for the lack of data must be provided. If unexpected results are obtained during clinical trials, additional preclinical toxicology and pharmacology studies must be conducted and the results must be reviewed;
j) If the medicinal product is intended for long-term use, the medicinal product registration dossier must describe changes in pharmacological action resulting from repeated administration of the medicinal product, and the choice of dosage for long-term use must be justified.
5.3. Clinical Trial Reports
5.3.1. Biopharmaceutical Study Reports
The medicinal product registration dossier must include reports on bioavailability, comparative bioavailability, bioequivalence, in vitro-in vivo correlation studies, and a description of the bioanalytical and analytical methods. Where bioequivalence is required to be demonstrated, information on the comparative bioavailability assessment must be included.
In the case of a biowaiver, the medicinal product registration dossier must include a report on in vitro studies. The assessment and conduct of bioequivalence studies, or justification for not conducting bioequivalence studies, must be presented in accordance with the requirements of the rules for conducting bioequivalence studies of medicinal products within the Eurasian Economic Union, approved by the Commission.
5.3.2. Reports of pharmacokinetic studies using human biomaterials.
Human-derived biomaterials include proteins, cells, tissues, and related materials derived from humans that are used in in vitro or in vivo studies to evaluate the pharmacokinetic properties of active substances. The registration dossier for a medicinal product must include reports on studies of the active substance binding to plasma proteins, hepatic metabolism, and interactions with the active substance, as well as studies using other human-derived biomaterials.
5.3.3. Human Pharmacokinetic Study Reports:
The registration dossier must describe the following pharmacokinetic characteristics:
Absorption (indicating the rate and extent);
Distribution;
Metabolism;
Excretion.
A description of clinically important characteristics (including the significance of kinetic data in determining the dosage regimen for patients at risk) and differences between humans and the animal species used in the preclinical studies must be provided. In addition to information on standard pharmacokinetic studies using a significant number of samples for population pharmacokinetic analysis based on sparse sampling during clinical trials, the registration dossier for a medicinal product may include information on the influence of intrinsic and extrinsic factors on the variability of the dose-response relationship of pharmacokinetic parameters.
Reports on pharmacokinetic studies and initial tolerability studies of the medicinal product in healthy volunteers and patients, reports on pharmacokinetic studies to assess the influence of intrinsic and extrinsic factors, and population pharmacokinetic reports must be provided.
If the medicinal product is coadministered with other medicinal products, the registration dossier for the medicinal product must include a description of the study of their concomitant use, which was conducted to demonstrate a possible change in pharmacological action. Information on the study of the pharmacokinetic interaction of the active substance with other medicinal products or substances must be provided.
5.3.4. Human pharmacodynamic study reports:
a) The registration dossier must confirm the correlation between pharmacodynamic action and efficacy, including:
the dose-response relationship and its development over time;
the justification for the dosing regimen and administration conditions;
the mechanism of action, if possible.
A description of the pharmacodynamic action unrelated to efficacy must be provided. Confirmation of pharmacodynamic effects in humans is not sufficient justification for the presence of any specific therapeutic effect;
b) If the medicinal product is used in combination with other medicinal products, a description of a study of their concomitant use, conducted to demonstrate a possible change in the pharmacological action of the medicinal product, must be provided. Information on the study of the pharmacodynamic interaction of the active substance with other medicinal products or substances must be included.
5.3.5. Efficacy and Safety Study Reports.
5.3.5.1. Reports of Controlled Clinical Trials Confirming the Stated Indications for Use.
Information on clinical trials must be provided. These trials, if possible, must be randomized and controlled, and in which the investigational medicinal product is compared with a placebo and/or a medicinal product with proven therapeutic efficacy. The use of any other study design must be justified. The choice of control groups in each specific case depends on ethical considerations and the scope of application. Therefore, in some cases, it is more appropriate to compare the efficacy of a new medicinal product with that of a medicinal product with proven (established) therapeutic efficacy, rather than with a placebo.
When presenting the assessment, measures must be taken to avoid bias, including randomization and blinding methods. The study protocol included in the medicinal product registration dossier must include a description of the statistical methods used, the number of patients and the reasons for their inclusion in the clinical trial (including power calculations), the significance level applied, and a description of the statistical unit (the statistical parameters used). Measures taken to avoid biased evaluation (especially randomization methods) must be adequately justified and documented. Information about the inclusion of a large number of patients in a clinical trial is not an equivalent substitute for a properly controlled study.
When analyzing safety data, consideration should be given to circumstances that led to dosage adjustments or the need for concomitant use of another medicinal product, serious adverse events, events that led to withdrawal from the clinical trial, and events that resulted in death. Patients or patient groups in the study with increased risk should be identified, with particular attention paid to potentially vulnerable groups in which the number of patients may be small (e.g., children, pregnant women, elderly patients with compromised health, patients with significant metabolic or excretory disorders, etc.). A final safety assessment should be described for the potential uses of the medicinal product.
5.3.5.2. Reports of uncontrolled clinical trials, reports of data analyses from multiple studies, and reports of other clinical trials.
These reports should be included in the registration dossier of the medicinal product.
5.3.6. Reports of post-marketing experience.
If a medicinal product is already registered in other countries, the medicinal product registration dossier must include information on adverse reactions to the medicinal product in question and medicinal products with the same active substance (if possible, in comparison with their clinical use).
5.3.7. Case Reports and Patient Lists.
The medicinal product registration dossier must be accompanied by case report reports and patient lists. These must be submitted in the same manner as clinical trial reports, indexed by study and maintaining the confidentiality of the personal data of the study patients.
The registration dossier must also include data from laboratory and instrumental research methods, as well as statistical analysis of the clinical trial results.
II. Special Requirements for Drug Registration Dossier Modules
6. Requirements for Registration Dossier Documents for Generic Drugs
The registration dossier for a generic medicinal product is submitted in accordance with the requirements of this section, taking into account the rules for conducting bioequivalence studies of medicinal products within the Eurasian Economic Union, approved by the Commission.
The selection of a reference product in bioequivalence studies is carried out in accordance with the rules for conducting bioequivalence studies of medicinal products within the Eurasian Economic Union, approved by the Commission.
The bioequivalence of a generic medicinal product to the original medicinal product must be demonstrated by appropriate bioavailability studies in accordance with the rules for conducting bioequivalence studies of medicinal products within the Eurasian Economic Union, approved by the Commission.
The general characteristics of the medicinal product and the instructions for medical use of the generic medicinal product must correspond to the general characteristics of the medicinal product and the instructions for medical use of the original medicinal product. If the indications for use differ from the original medicinal product in terms of an expanded dosage regimen, dosage regimen, or route of administration, the instructions for medical use of the generic medicinal product must include the results of relevant clinical studies.
6.1. Module 1.
In Section 1.8.2 of the registration dossier for the generic medicinal product, the applicant must provide a summary (up to 5 pages) of the justification and facts demonstrating that the medicinal product is a generic medicinal product of the corresponding original medicinal product. This summary must contain information about the product, its qualitative composition and quantitative content of the active substance, its dosage form, and the safety and/or efficacy profile of its active substance compared to the active substance of the original medicinal product, as well as, if necessary, information on the bioavailability and bioequivalence of this product.
In certain cases, a risk management plan may be required.
If some of the elements listed in this paragraph are missing from the summary, a justification for their absence must be provided in the corresponding section of the registration dossier for the medicinal product.
6.2. Module 2.
The preclinical and clinical data review should include:
a summary of the impurity profile of the active substance (and, where applicable, potential degradation products formed during storage of the medicinal product) in batches of the medicinal product to be marketed;
an assessment of bioequivalence studies or an explanation of why bioequivalence studies were not conducted;
updated literature on the active substance of the medicinal product (this requirement may be met by providing references to publications in peer-reviewed journals);
previously unknown points in the general characteristics of the medicinal product or points arising from the characteristics of the drug and/or its therapeutic group, which should be analyzed in the preclinical and clinical reviews (summaries) and supported by evidence from the scientific literature and/or evidence obtained as a result of additional studies;
additional information proving that the safety and/or efficacy profiles of the claimed drug do not differ from those of the reference drug in the event of differences in the chemical forms of the active substance (salts, esters, isomers, mixtures of isomers, complexes or derivatives of the active substance of the reference drug).
6.3. Module 3.
Module 3 of the medicinal product registration dossier must be submitted in full.
6.4. Module 4 and Module 5.
Results of bioequivalence studies conducted, where necessary, should be included in Section 5.3.1 of the medicinal product registration dossier. Results of demonstrating equivalence according to the biowaiver should be presented in Subsection 5.3.1.2. A bioanalytical method validation report must also be submitted. Data on concentration, pharmacokinetics, and statistical analysis must also be provided.
The bioequivalence study report must include information about the investigator (including their place of work), the organization where the studies were conducted, and the study duration. Audit certificates (if any) must be attached to the report.
The bioequivalence study report or a separate official letter must confirm the selection of the reference medicinal product in accordance with the rules for conducting bioequivalence studies of medicinal products within the Eurasian Economic Union, approved by the Commission. The following information about the reference medicinal product must also be provided:
trade name;
strength;
dosage form;
marketing certificate holder;
date of registration;
marketing certificate number;
member state in which the reference medicinal product is registered;
batch number;
manufacturer's name;
expiration date;
country of purchase.
A recommendation from the Expert Committee on Medicinal Products on the selection of the reference medicinal product (if any) must be provided.
The name and composition of the test product, batch size, manufacturing date, and, if possible, expiration date must be indicated.
The study report appendix also includes certificates of analysis for the reference and test products used in the bioequivalence study.
An official letter signed by the manufacturer's authorized quality representative confirming that the quantitative composition and manufacturing process of the test product are identical to the quantitative composition and manufacturing process of the medicinal product submitted for registration should be submitted.
Additional information (in accordance with the structure of the general technical document of the medicinal product registration dossier) should be provided demonstrating that the safety and/or efficacy profiles of the submitted medicinal product do not differ from those of the reference product in the event of differences in the chemical forms of the active substance (salts, esters, isomers, mixtures of isomers, complexes, or derivatives of the active substance of the reference product).
Results of preclinical and clinical studies of the generic medicinal product, conducted where necessary, should be included in the relevant sections of Module 4 and Module 5.
Bioavailability studies are not required if there is evidence that the generic medicinal product meets the criteria specified in the rules for conducting bioequivalence studies of medicinal products within the Eurasian Economic Union, approved by the Commission.
If the active substance of the generic medicinal product is a different salt, ester, or derivative of the active substance of the registered medicinal product, additional information (bibliographic reviews) or reports of relevant preclinical and/or clinical studies (comparative bioavailability studies) demonstrating the absence of changes in the pharmacokinetics, pharmacodynamics, and/or toxicity of the generic medicinal product must be provided. If such evidence is not provided, this substance is considered a new active substance.
7. Requirements for the registration dossier of a hybrid medicinal product
The registration dossier for a hybrid medicinal product must contain additional data from preclinical and clinical studies in accordance with the requirements of this section.
7.1. Module 1.
In Section 1.8.2 of the registration dossier for a generic medicinal product, the applicant must provide a summary (up to 5 pages) of the justification and facts demonstrating that the medicinal product is a hybrid medicinal product relative to the corresponding original medicinal product. The summary must include information about the product, active pharmaceutical ingredient, dosage form, dosage, indications for use, route of administration compared to the original medicinal product, and, if necessary, information on the bioavailability and bioequivalence of this product.
If certain elements are missing, a justification for their absence must be provided in the section of the registration dossier for the medicinal product corresponding to the location of the element.
7.2. Module 2.
The review of preclinical and clinical data should pay particular attention to the following elements:
a summary of the impurity profile of the active substance (and, where applicable, possible degradation products formed during storage of the medicinal product) in batches of the medicinal product to be marketed;
updated literature on the active substance of the medicinal product (this requirement may be met by providing references to articles in peer-reviewed journals);
previously unknown points in the general characteristics of the medicinal product or points arising from the characteristics of the drug and/or its therapeutic group, which should be analyzed in preclinical and clinical reviews (summaries) and supported by evidence from the scientific literature and/or evidence obtained as a result of additional studies;
additional information demonstrating that the safety and/or efficacy profiles of the proposed medicinal product do not differ from those of the reference medicinal product in the event of different chemical forms of the active substance (salts, esters, isomers, mixtures of isomers, complexes, or derivatives of the active substance of the reference medicinal product).
7.3. Module 3.
7.4. Module 4 and Module 5.
Results of preclinical and/or clinical trials of the hybrid medicinal product should be included in the relevant sections of Module 4 and Module 5.
Procedure for conducting additional studies required for
generic and hybrid medicinal products or
for registration applications with extended requirements
Characteristics of medicinal products or applications for registration
Additional data required
Various salts, esters, complexes, and their derivatives (with the same active moiety)
Evidence that there are no changes in the pharmacokinetics of the active moiety, pharmacodynamics, and/or toxicity that could significantly affect the safety and/or efficacy profile (otherwise, the active substance should be considered a new active substance)
Different route of administration or different dosage form:
New route of administration (for parenteral administration, distinctions must be made between intra-arterial, intravenous, intramuscular, subcutaneous, and other routes of administration)
Different dosage form (with the same route of administration)
Clinical data (safety and efficacy), pharmacokinetics, and relevant preclinical data (e.g., local tolerability) (if available)
Different dosage with the same route of administration (dosage form) and indications for use
Comparative bioavailability data in accordance with the rules for conducting bioequivalence studies of medicinal products within the Eurasian Economic Union, approved by the Commission
Super-bioavailable drugs, maintaining the same dosing interval but with a reduced dose, designed to achieve similar plasma (blood) concentrations
In certain cases, comparative bioavailability studies in accordance with the rules for conducting bioequivalence studies of medicinal products within the Eurasian Economic Union, approved by the Commission, are sufficient
8. Requirements for registration dossier documents for
medicinal products with well-studied medical use
The following special rules apply to medicinal products with confirmed efficacy and an acceptable level of safety (which include, for example, medicinal products made from raw materials of natural origin (birch tar, snake venom, bee products, medicinal leeches, bile, minerals, etc.), whose active substance has been well studied in medical use, vitamins and vitamin-mineral complexes, as well as medicinal products whose pharmacological activity is determined by a complex of biologically active substances of natural origin, antiseptic solutions (hydrogen peroxide, iodine, brilliant green, etc.), water for injection, adsorbents (activated carbon, etc.), carminative medicinal products, and medicinal products from the group of irritants and enveloping agents).
The applicant must submit Module 1, Module 2, and Module 3 of the registration dossier of the medicinal product in accordance with the requirements of Part I of these Requirements.
In Modules 4 and 5, the detailed scientific bibliography must include the preclinical and clinical characteristics of medicinal products.
To confirm well-studied medical use, the following data must be provided:
a) Factors that must be taken into account when determining the well-studied medical use of medicinal product components:
the period during which the active substance has been used in medical practice;
quantitative aspects of the use of the active substance;
frequency of scientific publications and the relevance of the use of the active substance in the 5 years prior to the date of filing the application for registration of the medicinal product (with reference to publications in scientific sources);
consistency of scientific assessments.
To determine the well-studied medical use of different active substances, assessments may be made over different time periods. The period of time required to determine the well-studied medical use of the active substance must be at least 10 years from the date of its documented use in at least three Member States. Biological medicinal products and medicinal products that require bioequivalence studies and/or clinical trials are not considered to be medicinal products with well-studied medical use;
b) The registration dossier materials submitted by the applicant must include documents and data on all aspects of the safety and efficacy assessment, containing or providing a reference to a review of the relevant literature, taking into account pre- and post-registration studies and published scientific literature regarding the results of epidemiological studies, and especially comparative epidemiological studies, all documentation (both with positive assessment results and with negative results of the medicinal product assessment). Bibliographic references to other sources of evidence of the efficacy and safety of the medicinal product (post-registration studies, epidemiological studies, etc.), with the exception of data related to control and testing methods, may be evidence of the safety and efficacy of the medicinal product, provided that the registration dossier clearly explains and justifies the use of these sources of information;
c) The documents and data of the registration dossier of the medicinal product must substantiate why an acceptable level of safety and/or efficacy can be considered proven despite the absence of some studies;
d) In the preclinical and/or clinical reviews of Module 2 of the medicinal product registration dossier, it is necessary to explain the significance of any data presented for the medicinal product proposed for registration if they differ from the data of an already registered medicinal product. It is necessary to provide a justification for whether the proposed medicinal product can be considered similar to the already registered medicinal product despite the existing differences;
e) Post-registration experience with the medicinal product may be presented in the form of information on the use of other medicinal products containing the same active substances;
f) If the medicinal product has experience in third-country markets, a periodic safety update report must be submitted for the medicinal product for 5 years prior to the date of filing the registration application.
9. Requirements for the Registration Dossier of Combination
of Medicinal Products
For new medicinal products that are a combination of two or more previously known active substances in a single dosage form (i.e., active substances included in a combination medicinal product but previously registered in single-component products), a full registration dossier (Modules 1-5) must be submitted in accordance with Part I of these Requirements. Module 3 includes information on the production, quality control, and manufacturer of each active substance included in the combination medicinal products (single-component medicinal products presented in combination packaging cannot be considered combination medicinal products). Modules 4 and 5 present the results of preclinical and clinical studies of the active substance combinations submitted for registration.
When preparing the registration dossier for a combination medicinal product, as well as when reviewing the relevant registration dossier documents, the provisions of the acts of Union bodies in the field of preclinical and clinical development of combination medicinal products are followed.
(paragraph introduced by Decision No. 60 of the Council of the Eurasian Economic Commission dated May 22, 2023)
10. Requirements for the Registration Dossier
of a Biosimilar (Biosimilar) Medicinal Product
To register a biosimilar (biosimilar) medicinal product, data from comparative studies of it with a reference biological medicinal product must be submitted. The quality, safety, efficacy, and immunogenicity of the biosimilar (biosimilar) medicinal product during the manufacturing, preclinical, and clinical phases of its development must be compared with the same reference biological medicinal product in accordance with the rules for the study of biological medicinal products within the Eurasian Economic Union, approved by the Commission. The registration dossier for a biosimilar medicinal product is submitted in accordance with the requirements of this section.
10.1. Module 1.
10.1.1. In Section 1.8.2 of Module 1 of the registration dossier, the applicant must provide a summary of the justifications and facts demonstrating that the medicinal product for which the application is submitted is a biosimilar medicinal product to the original medicinal product. The summary must contain information on the medicinal product, active substance, dosage form, dosage, indications for use, and route of administration, compared with similar information on the original medicinal product.
10.1.2. In Section 1.10 of Module 1 of the registration dossier, a risk management plan for the biosimilar medicinal product being submitted for registration is submitted along with brief information on the marketing authorization holder's pharmacovigilance system.
10.1.3. If certain elements of the registration dossier are missing, a justification for their absence should be provided in the relevant section of this module.
10.2. Module 2.
The quality data review, preclinical data review, and clinical data review must additionally provide comparative information on the proposed medicinal product and the reference medicinal product, as well as the criteria for selecting the reference medicinal product and their rationale.
The study report or a separate official letter must confirm the selection of the reference medicinal product in accordance with the rules for conducting trials of biological medicinal products within the Eurasian Economic Union, approved by the Commission. The following information about the reference medicinal product must also be provided:
(as amended by Decision of the Council of the Eurasian Economic Commission dated 30.01.2020 N 9)
strength and dosage form;
name of the marketing authorization holder;
date of registration and number(s) of the marketing authorization;
member states in which the reference medicinal product is registered;
batch number of the reference medicinal product used for research and pharmaceutical development;
Name of manufacturer;
Expiration date;
Country of purchase.
If available, a recommendation from the Expert Committee on Medicinal Products regarding the selection of the reference product must be provided.
The name and composition of the study product(s), batch size, manufacturing date, and, if possible, expiration date must be indicated.
A justification for the scope of comparative preclinical and/or clinical studies conducted must be provided based on the requirements of the rules for conducting biological medicinal product trials within the Eurasian Economic Union, approved by the Commission. Copies of the batch analysis certificates for the reference and study products used in the study must be attached to the study report.
10.3. Module 3.
In Module 3 of the medicinal product registration dossier, the following additional data must be provided, taking into account the requirements of the rules for conducting biological medicinal product trials within the Eurasian Economic Union, approved by the Commission:
a) confirmation of the similarity of the molecular and biological characteristics of the active substances of the biosimilar medicinal product and the reference biological medicinal product (data on the primary and higher-order structures, post-translational modifications (including, in particular, glycoforms), biological activity, purity, and impurities);
b) confirmation of the similarity of the medicinal product characteristics (dosage form, quantitative and qualitative composition, dosage, route of administration, storage conditions, shelf life, stability, and impurity profile) of the biosimilar and the reference biological medicinal product;
c) if there are differences in impurities and excipients, their potential impact on the clinical safety and efficacy profile of the biosimilar must be assessed and the acceptability of these differences must be justified (based on the results of the company's own research or data provided in the scientific literature); if there are differences whose clinical significance is unknown, especially in terms of safety, additional studies are required in the pre- and post-registration period;
d) a complete description and data on the manufacturing process (starting with the development of expression constructs (systems), the original producer strain and cell banks, cell culture (cultivation), collection, purification, additional manufacturing processes after product isolation and purification, filling of containers for bulk product and finished dosage form, and ending with storage);
e) data on studies conducted during the pharmaceutical development of a biosimilar medicinal product to determine and justify its dosage form, composition, and packaging (closure) system (including their integrity to prevent microbial contamination);
f) specification of the biosimilar medicinal product, which must contain and regulate the important quality parameters of the medicinal product established for the reference biological medicinal product (such as identity, purity, potency, molecular heterogeneity in terms of size, charge, and hydrophobicity (where these can be determined), degree of sialylation, number of individual polypeptide chains, glycosylation of the functional region, degree of aggregation, impurities such as host cell protein and DNA, etc.);
g) stability studies.
10.4. Module 4.
Module 4 should present the results of preclinical (non-clinical) studies of a biosimilar medicinal product compared to a reference biological medicinal product in accordance with the requirements of the rules for conducting studies of biological medicinal products within the Eurasian Economic Union, approved by the Commission.
10.5. Module 5.
Module 5 presents documents and data in accordance with the requirements of the rules for conducting studies of biological medicinal products within the Eurasian Economic Union, approved by the Commission, which contain:
a) the results of clinical trials of a biosimilar medicinal product in comparison with a reference medicinal product, which include:
the results of pharmacokinetic studies (single-dose pharmacokinetic studies, repeated-dose pharmacokinetic studies (if there is a dose- and time-dependent pharmacokinetic comparison of a biosimilar medicinal product and a reference medicinal product) should include a study of absorption, bioavailability, elimination characteristics, i.e., clearance and/or half-life), pharmacodynamic studies (in this case, pharmacodynamic effects should be assessed in a suitable population and using doses from the steep part of the dose-response curve obtained in preclinical studies, and pharmacodynamic markers should be selected depending on their clinical significance));
data from comparative clinical studies, including an assessment of the type, frequency, and severity of adverse events (reactions), immunogenicity studies in the target group (comparison of the frequency and type of antibodies formed, potential clinical consequences of the immune response for the biosimilar drug and the reference drug); immunogenicity should be studied in the patient population with the highest risk of an immune response and immune-related adverse reactions;
justification of the antibody determination strategy, including the selection, evaluation, and characterization of methods, establishment of sample collection time (including before drug administration), sample volumes, processing, and storage, as well as statistical methods for data analysis; analytical methods for antibody determination should be validated for the chosen research purpose; a preliminary analysis of sufficient method sensitivity should be conducted; neutralizing antibodies should be determined;
indication of the observation period during immunogenicity studies (which must correspond to the planned duration of treatment and the expected time of antibody formation and must not be less than 12 months (if the study duration is different, justification must be provided));
Clinically significant cases of antibody titer formation and titer maintenance over a certain period of time (while it is necessary to study potential changes in the nature of the immune response and clinical consequences in the pre- and post-registration periods);
The main clinical data must be obtained using the medicinal product manufactured using the final manufacturing process, i.e., the medicinal product for which the registration application is submitted. For any deviations from these requirements, the applicant must provide justification and, if necessary, data from additional comparability studies conducted in accordance with the rules for conducting studies of biological medicinal products within the Eurasian Economic Union, approved by the Commission for the medicinal product with the final and earlier formulation;
b) a risk management plan, including a safety specification (with a description of the important identified and potential negative safety aspects of the reference drug, class of drugs and (or) biosimilar) and a pharmacovigilance plan for the biosimilar drug in the post-registration period (with a description of the planned post-registration activities and measures to minimize the risk based on the safety specification, the risk management plan, including the provision of information materials for patients and (or) medical and pharmaceutical workers).
11. Registration dossier for registration applications
(as amended by Decision No. 36 of the Council of the Eurasian Economic Commission
dated March 17, 2022)
A marketing authorization for a medicinal product is granted subject to the fulfillment of specific obligations if the applicant can demonstrate (justify) that it is impossible to provide comprehensive data on the efficacy and safety of the medicinal product under normal conditions of use for one of the following reasons:
the proposed indications for the medicinal product are so rare that the applicant cannot reasonably expect to receive comprehensive confirmation of the evidence for the efficacy and safety of the medicinal product;
the current state of scientific knowledge does not permit the provision of comprehensive information on the efficacy or safety of the medicinal product;
obtaining information on the efficacy or safety of the medicinal product would be contrary to generally accepted principles of medical ethics.
These obligations include the following:
the applicant must complete, within the timeframe established by the competent authority of the reference Member State, a defined safety or efficacy study program, the results of which allow for a reassessment of the benefit-risk balance;
The medicinal product in question must be classified as a "prescription drug" and, in certain cases, only used under strict medical supervision (e.g., in a hospital setting). For radiopharmaceuticals, this means use under the supervision of an appropriately authorized person.
The general characteristics of the medicinal product, the instructions for medical use of the medicinal product (package insert), the registration certificate, and any medical information must contain information that draws the user's attention to the fact that the available data on the medicinal product are insufficient to support certain aspects of safety or efficacy.
11.1. Requirements for the composition of the registration
dossier submitted as part of the procedure for bringing it into compliance
with the Union's requirements
(introduced by Decision No. 114 of the Council of the Eurasian Economic Commission
dated October 20, 2023)
As part of the procedure for bringing an application into compliance with Union requirements, the applicant shall submit, as part of Module 1 of the registration dossier, the documents specified in Sections and Clauses 1.0, 1.1, 1.2.1, 1.2.2, 1.3, 1.3.1, 1.3.2, 1.5.3, 1.5.4, 1.5.7, 1.6.1, 1.6.2, 1.6.7, 1.6.9, 1.6.11, 1.10, 1.10.1, and 1.10.2 of these Requirements.
If necessary, the documents listed in Clauses 1.3.4, 1.5.5, 1.5.6, 1.8.2.6, 1.9.1, 1.10.3, and 1.10.4 of these Requirements shall also be submitted.
Module 2 of the registration dossier may be submitted in the form of summary sections with updated amendments (in the form of an appendix) or submitted in full at the applicant's initiative.
As part of the procedure for bringing the registration dossier into compliance with Union requirements, the submission of the documents specified in paragraphs 3.2.S.2.3–3.2.S.2.6, 3.2.S.4.3, 3.2.S.4.5, 3.2.S.7.2, 3.2.P.2.2.3, 3.2.P.2.3–3.2.P.2.6, 3.2.P.4.3, 3.2.P.4.6, 3.2.A, 3.2.A.2, 3.2.A.3, 3.2.A.3.3, and 3.2.A.3.7 of these Requirements is optional (with the exception of the registration dossier of biological medicinal products). If they are not submitted within the specified procedure, the documents must be submitted as part of the registration confirmation or when making changes to the registration dossier.
Data from preclinical and clinical studies conducted in accordance with the legislative requirements of Member States are presented in Modules 4 and 5 of the medicinal product registration dossier as reports without the mandatory procedure of aligning with Union requirements and are attached to the reports on preclinical (non-clinical) studies and clinical studies (trials) of the medicinal product.
The requirements for registration dossier documents for individual groups of drugs, as set out in Modules 4 and 5, are provided for in Sections II - IV of these Requirements.
As part of the aligning procedure with Union requirements, the authorized body (expert organization) of a Member State has the right to request information available from the applicant upon request during the examination of the medicinal product registration dossier (if necessary).
III. Special Requirements for Registration
Dossier Documents for Certain Types of Medicinal Products
12. Biological Medicinal Products
Module 3 of the registration dossier for vaccines and blood products is compiled taking into account the specific features of these medicinal products specified in this section.
12.1. Plasma-Derived Medicinal Products
For medicinal products derived from human blood or plasma, the requirements for starting materials and raw materials derived from human blood (plasma) may be replaced by a plasma master file compliant with this section, as an exception to the general requirements for Module 3 of the registration dossier presented in Part I of these Requirements.
12.1.1. General Principles for Compiling the Registration Dossier
For the purposes of these Requirements:
the plasma master file is an independent document, separate from the medicinal product registration dossier, containing all relevant detailed information on the characteristics of all human plasma used as starting material and/or raw materials in the production of subfractions or intermediate fractions, components of excipients, or active substances that are part of medicinal products or medical devices;
each center or institution fractionating (processing) human plasma must prepare and maintain an updated set of detailed relevant information specified in the plasma master file;
the plasma master file must be submitted by the applicant or marketing authorization holder to the authorized body of the Member State on paper or as an electronic document. If the applicant or marketing authorization holder is not the owner of the master file, the master file must be available to the applicant or marketing authorization holder for submission to the authorized bodies of the Member States. In any case, the applicant or marketing authorization holder is responsible for the quality, safety, and efficacy of the medicinal product;
If the registration dossier pertains to a plasma-derived component, then the plasma used as the starting material (raw material) must be referenced to the owner's master file.
12.1.2. Additional Requirements for the Contents of Registration Dossier Materials.
The owner's master file must contain the following information about the plasma used as the starting material (raw material):
Origin of the plasma:
Information on the centers or institutions where blood (plasma) is collected, including inspection data and the submission of a special permit for this type of activity, as well as epidemiological data on blood-borne infections in the region where the blood (plasma) is collected;
Information on the centers or institutions where donations and plasma pools are monitored, including the inspection and regulatory status of these centers or institutions;
Criteria for the selection (exclusion) of blood (plasma) donors;
A description of the current system that allows for tracking the path of each donation from the institution where the blood (plasma) is collected to the finished medicinal product and vice versa;
Plasma quality and safety:
quality compliance with the articles (monographs) of the Eurasian Economic Union Pharmacopoeia or, if absent, with the articles (monographs) of the state pharmacopoeias of the member states or the main pharmacopoeias in accordance with the Concept of Harmonization of Pharmacopoeia of the Eurasian Economic Union Member States;
testing of collected blood (plasma) and its pools for the presence of infectious agents, including information on the testing methods and, in the case of plasma pools, validation data for the methods used;
technical specifications of blood and plasma collection containers, including information on the anticoagulant solutions used;
plasma storage and transportation conditions;
storage procedure for any material used for production and/or quarantine period;
plasma pool characteristics;
A description of the established system of interaction between the manufacturer of a plasma-derived medicinal product and/or the center or institution fractionating and/or processing the plasma and the center or institution collecting and testing blood (plasma), as well as the plasma specifications agreed upon between them.
The plasma master file must also contain a list of the medicinal products it covers, regardless of whether these medicinal products are registered, are in the registration process, or are in clinical trials.
12.1.3. Review of the registration dossier and issuance of an opinion.
For unregistered medicinal products, the applicant must submit to the authorized body of the Member State the complete registration dossier of the medicinal product, which will be accompanied by a separate plasma master file, if one has not previously been compiled and submitted.
The plasma master file is subject to review as part of the registration and review of the medicinal product's registration dossier. If the review results are positive, a Union opinion (certificate) is issued for the master file, which must be accompanied by an expert report. The issued opinion (certificate) is valid throughout the Union.
The plasma master file is subject to annual renewal and re-evaluation.
If changes are made to the plasma master file, it is subject to review in accordance with the amendment procedure.
The issued opinion (certificate) is accepted by the authorized bodies of the Member States during registration procedures (confirmation of registration, amendments to the registration dossier) of medicinal products derived from human plasma (blood).
12.2. Vaccines
For vaccines for human use, as an exception to the general requirements for Module 3 of the "Active Pharmaceutical Substance" registration dossier, the following requirements apply based on the use of the Vaccine Antigen Master File system.
A registration dossier for a vaccine other than a human influenza vaccine must include a Vaccine Antigen Master File for each antigen that constitutes the active substance of that vaccine.
12.2.1. General Principles.
The Vaccine Antigen Master File is a separate part of the vaccine registration dossier that contains all relevant biological, pharmaceutical, and chemical information regarding each of the active substances that comprise the medicinal product. This separate part may be common to one or more monovalent and/or combination vaccines submitted by the same applicant or marketing authorization holder.
A vaccine may contain one or more different vaccine antigens. The number of active substances in a vaccine corresponds to the number of vaccine antigens. A combination (polyvalent) vaccine contains at least two different vaccine antigens intended to prevent one or more infectious diseases.
A monovalent vaccine is a vaccine that contains one vaccine antigen intended to prevent one infectious disease.
12.2.2. Additional Requirements for the Contents of Registration Dossier Materials.
The vaccine antigen master file must contain the following information, extracted from the relevant section (Active Pharmaceutical Substance) of Module 3 "Quality," as described in Part I of this Appendix.
Active Substance
1. General information, including information on compliance with the article (monograph) of the Pharmacopoeia of the Eurasian Economic Union, or, in the absence of such articles (monographs), articles (monographs) of the pharmacopoeias of the Member States or the primary pharmacopoeias in accordance with the Concept of Harmonization of Pharmacopoeias of the Member States of the Union.
2. Information about the manufacturer of the active substance: information about the production process, starting materials and raw materials, special measures regarding spongiform encephalopathies and safety assessment of foreign infectious agents, premises and equipment.
(as amended by Decision No. 60 of the Council of the Eurasian Economic Commission dated May 22, 2023)
3. Characteristics of the active substance.
4. Quality control of the active substance.
5. Standard samples and materials.
6. Primary packaging and closure system of the active substance.
7. Stability of the active substance;
c) Excluded. - Decision of the Council of the Eurasian Economic Commission dated January 30, 2020, No. 9.
For new vaccines containing a new vaccine antigen, the applicant must submit to the authorized body a complete registration dossier, including all vaccine antigen master files for each vaccine antigen that is part of the new vaccine, if a vaccine antigen master file for such vaccine antigen is not available. If the examination results are positive, a Union certificate is issued for the master file, which must be accompanied by an expert report. The issued certificate is valid throughout the territory of the Union. These requirements also apply to each vaccine that consists of a new combination of vaccine antigens, regardless of whether one or more of these antigens are part of vaccines already registered in Member States.
When changes are made to the vaccine antigen master file, the master file is subject to review in accordance with the amendment procedure.
The issued conclusion (certificate, attestation) of the Union is accepted by authorized bodies during vaccine registration procedures (confirmation of registration, amendments to the registration dossier).
12.2.3. Review and issuance of conclusions.
(Clause 12.2.3 introduced by Decision No. 9 of the Council of the Eurasian Economic Commission dated 30.01.2020)
12.3. Simplified Registration Dossier for Vaccines
with Well-Studied Medical Use, Manufactured
in Member States Before 2000
The following rules apply to vaccines whose vaccine antigen has been well-studied for medical use, with confirmed efficacy and an acceptable level of safety, and manufactured in Member States before 2000.
The applicant must complete Module 3 of the registration dossier in accordance with the provisions of Part I and Section 12.2 of Part II of this Appendix.
In Modules 4 and 5 of the registration dossier, instead of preclinical and clinical study reports, a scientific review bibliography is submitted, which must include the preclinical and clinical characteristics of the vaccine.
13. Radiopharmaceuticals and Precursors
The registration dossier for radiopharmaceuticals and their precursors is submitted in accordance with the requirements of this section.
13.1. Radiopharmaceuticals
13.1.1. Module 3.
In a radiopharmaceutical kit that is radiolabeled after delivery by the manufacturer, the "active substance" means the part of the kit intended to carry or bind the radionuclide. The description of the radiopharmaceutical kit manufacturing method must include detailed data on the kit production and the recommended final processing for the production of the radiopharmaceutical. The required radionuclide specifications must be described in accordance with the general or specific monograph of the Pharmacopoeia of the Eurasian Economic Union (if such monograph exists) or, in the absence of such monographs, in accordance with the monographs of the pharmacopoeias of the Member States or the primary pharmacopoeias in accordance with the Concept of Harmonization of Pharmacopoeias of the Member States of the Union.
All compounds required for radiolabeling, as well as the structures of the radiolabeled compounds, should be described.
Nuclear reactions of the radionuclides must be analyzed.
The parent and daughter radionuclides of the generator are considered active substances.
Information on the nature of the radionuclide, isotope identity, possible impurities, carrier, application, and specific activity must be provided.
Source materials include the target materials for irradiation.
Chemical (radiochemical) purity and its relationship to biodistribution must be considered.
Radionuclide purity, radiochemical purity, and specific activity must be described.
For generators, detailed test data for the parent and daughter radionuclides are required. For generator-eluates, test results for the parent radionuclides and other components of the generator system must be provided.
The content of active substances should be expressed based on the mass of the active moiety of the molecule only for radiopharmaceutical kits. For radionuclides, radioactivity must be expressed in becquerels, with the date and, where appropriate, the time and time zone. The type of radioactivity must be specified.
Specifications for a medicinal product that is a radiopharmaceutical kit must include test results for the properties of the product after incorporation of the radioactive label. Appropriate controls for the radiochemical and radionuclide purity of the radiolabeled compound must be included. Any material required for incorporation of the radioactive label must be identified and quantified.
Stability information must be provided for isotope generators, isotope kits, and radiolabeled medicinal products. Stability must be specified when using radiopharmaceuticals in reusable containers.
13.1.2. Module 4.
Toxicity may be related to the radiation dose. In diagnostics, toxicity is an undesirable consequence of the use of radiopharmaceuticals; In therapy, this is a desirable property; therefore, when assessing the safety and efficacy of radiopharmaceuticals, it is necessary to specify drug product requirements and radiation dosimetry aspects. The effect of radiation on the human organ (tissue) must be documented. The absorbed dose of radiation must be calculated using the system of internationally recognized units of measurement used for a specific route of administration.
13.1.3. Module 5.
Clinical trial results are provided, if necessary. The absence of clinical trial results is justified in clinical reviews (Module 2 of the registration dossier).
13.2. Radiopharmaceutical precursors used for radiolabeling.
For a radiopharmaceutical precursor intended solely for radiolabeling, information must first be provided on the potential consequences of insufficient radiolabeling efficiency or in vivo dissociation of the radiolabeled conjugate—that is, issues related to the effects of the free radionuclide on patients. In addition, relevant information regarding risk factors, i.e., radiation exposure to hospital personnel and the environment, must also be provided.
Specifically, the following information must be provided:
13.2.1. Module 3.
The requirements for the content of Module 3 of the registration dossier specified in Section 3 of Part I of this Appendix shall be applied to the registration of radiopharmaceutical precursors insofar as subparagraphs "a" through "i" are applicable.
13.2.2. Module 4.
Regarding single- and multiple-dose toxicity, the results of preclinical studies conducted in accordance with the rules of good laboratory practice approved by the Commission must be provided. Mutagenicity studies of radionuclides are not considered applicable in this case.
Information on the chemical toxicity and disposition of the "cold" nuclide (containing no radioactive substances) must be provided.
13.2.3. Module 5.
Clinical information obtained during clinical trials using the precursor itself is not considered relevant in the case of a radiopharmaceutical precursor intended solely for the introduction of a radioactive label. Information confirming the clinical efficacy of the radiopharmaceutical precursor when attached to the corresponding carrier molecules must be provided.
14. Homeopathic Medicinal Products
14.1. Module 3.
Terminology.
The scientific name in Latin of the homeopathic pharmaceutical substance described in the registration dossier must correspond to the scientific name in Latin of the monograph of the Pharmacopoeia of the Eurasian Economic Union (if available), or the homeopathic pharmacopoeia of the Union member states, or the homeopathic pharmacopoeia of Germany, the French pharmacopoeia, and the European Pharmacopoeia.
Control of Source Materials.
The registration dossier must include documents confirming the quality of all components of the product, including the homeopathic pharmaceutical substance and excipients, meets the requirements of the references to monographs or regulatory documents provided in the "Composition" section. For homeopathic pharmaceutical substances, these are monographs of the Eurasian Economic Union Pharmacopoeia (if available) or the pharmacopoeias of the member states, or monographs of the German Homeopathic Pharmacopoeia, or monographs of the French Pharmacopoeia, or the European Pharmacopoeia; for excipients, these are the regulatory documentation or monographs of the aforementioned pharmacopeias.
Basic quality requirements must apply not only to all starting materials and raw materials but also to intermediate products (substance dilutions) up to the final dilution incorporated into the medicinal product. If a homeopathic pharmaceutical substance containing a potent or toxic active ingredient is used, the content of such an active ingredient must be determined by a suitable method and regulated accordingly (e.g., by bilateral standardization of the content of such an active ingredient or by testing the fourth decimal dilution). As a rule, dilutions above the D4 decimal scale and centesimal scale dilutions do not allow such an assessment. If dilutions of a homeopathic pharmaceutical substance are used to produce a homeopathic medicinal product, they are obtained in accordance with the methods and processes described in the relevant monograph of the Eurasian Economic Union Pharmacopoeia (if available), or in the monographs of the pharmacopoeias of the member states, or the monograph of the German Homeopathic Pharmacopoeia, the monograph of the French Pharmacopoeia, or the European Pharmacopoeia, and the dilution scale and degree are specified.
Control testing of the medicinal product.
Essential quality requirements must be applied to homeopathic medicinal products. If there are deviations from the essential quality requirements, the applicant must justify them.
If a homeopathic pharmaceutical substance containing a potent or toxic active ingredient is used in the production of a homeopathic medicinal product, testing must be conducted to establish the identity and quantify these substances in the homeopathic medicinal product (if necessary).
If there is justification for the impossibility of quantifying and/or identifying all toxicologically significant components (e.g., due to the degree of dilution in the medicinal product), quality must be confirmed by full validation of the manufacturing and dilution processes.
If a homeopathic pharmaceutical substance that does not contain a potent or toxic active ingredient is used in the production of a homeopathic medicinal product, testing must be conducted to establish the identity and quantify these substances in accordance with the monographs for homeopathic pharmaceutical substances of the specific name (if necessary).
Stability testing.
The stability of the medicinal product must be confirmed. Stability test data for the homeopathic source material are generally valid for dilutions and triturations prepared from this material. If quantification or identification of the active substance is not possible due to the degree of dilution, stability test data for the dosage form may be considered.
14.2. Module 4.
Preclinical Toxicity Study Data.
Any omissions must be justified, for example, by justifying how an acceptable safety profile can be confirmed in the absence of certain studies.
For new homeopathic medicinal products (matrix tinctures, triturations, and other components) not listed in pharmacopoeias and monographs: toxicology study data, justification for the selection of various dosages, and subsequent clinical trial data must be provided.
14.3. Module 5.
Clinical Trial Data, Post-Market Use (if any).
Any omissions must be justified, for example, by justifying how an acceptable efficacy and safety profile can be confirmed in the absence of certain studies. For homeopathic medicines (matrix tinctures, triturations, and other components) not listed in pharmacopoeias and monographs, clinical trial data (in accordance with the requirements of this appendix) and justification for the selection of various dosages are required.
For homeopathic medicines with many years of experience and included in pharmacopoeias, a review of scientific literature on the efficacy and safety of the homeopathic medicine in the stated area of use is required.
The general characteristics of the medicinal product and the instructions for medical use of the medicinal product include the statement: "homeopathic medicinal product."
14.4. Simplified Registration Dossier for Homeopathic Medicinal Products.
For registration of homeopathic medicinal products, a simplified registration dossier is submitted if the following conditions are met:
the medicinal product is intended for oral administration or for external, topical, or inhalation use;
the medicinal product packaging, SmPC, or UMP do not indicate a specific therapeutic indication for use;
the dilution level is sufficient to guarantee the safety of the medicinal product. Specifically, the medicinal product contains no more than 1/10,000 parts of a homeopathic substance (homeopathic mother tincture) or contains no more than 1/100 of the minimum dose used in allopathy, with respect to active ingredients whose presence in the medicinal product requires dispensing by prescription.
Evidence of therapeutic efficacy for these homeopathic medicinal products is not required. The dispensing category of such homeopathic medicinal products is established during registration.
An application for a special, simplified registration procedure may cover a series of medicinal products derived from the same homeopathic pharmaceutical substance or several homeopathic pharmaceutical substances of similar origin (e.g., animal, mineral, or plant origin).
(as amended by Decision No. 9 of the Council of the Eurasian Economic Commission dated 30.01.2020)
To confirm the pharmaceutical quality and homogeneity of the product from batch to batch, the application is accompanied by a registration dossier containing the following documents:
the scientific name in Latin of the homeopathic pharmaceutical substance, as specified in the pharmacopoeia, indicating the scale and degree of dilution, information on the routes of administration, dosage forms, and degree of dilution subject to registration;
One or more mock-ups of the consumer and primary packaging, as well as the general characteristics of the medicinal product and instructions for medical use (package insert) for homeopathic medicinal products submitted for the simplified registration procedure;
A dossier describing the method of obtaining and controlling the homeopathic pharmaceutical substance, raw material, or types of raw materials, and justifying the homeopathic use based on the relevant bibliography;
A description of the production and control for each dosage form, a description of the scale, and the dilution (potentization) method;
A license for the manufacture of medicinal products and a document confirming compliance with the rules of good manufacturing practice of the Union;
Copies of registration certificates for medicinal products under the simplified procedure obtained in other countries;
Stability data for the homeopathic medicinal product.
15. Herbal Medicinal Product
The registration dossier for herbal medicinal products shall be submitted in accordance with the requirements of this section.
15.1. Module 3.
When registering herbal medicinal products, the requirements for Module 3 specified in Section 3 of Part I of this Appendix must be applied, including the need to comply with the pharmacopoeial monographs of the Eurasian Economic Union Pharmacopoeia or the pharmacopoeias of the member states. Available scientific information as of the application submission date must be taken into account.
15.1.1. Herbal Pharmaceutical Substances.
(as amended by Decision No. 60 of the Council of the Eurasian Economic Commission dated 22.05.2023)
For the purposes of this Appendix, the term "herbal pharmaceutical substance" is general, encompassing the concepts of "medicinal plant material" and "product made from medicinal plant material."
For herbal pharmaceutical substances obtained after grinding medicinal plant material, the following must be indicated: the binomial scientific name of the producing plant: genus and species, variety and author in Latin, chemotype (if necessary), source of origin (wild or cultivated), morphological group of the producing plant, and the name (definition) of the herbal pharmaceutical substance.
For a herbal pharmaceutical substance obtained after processing medicinal plant materials by various methods (extraction, distillation, pressing, fractionation, purification, concentration, fermentation, etc.), it is necessary to indicate the binomial scientific name of the producing plant: genus and species, variety and author in Latin, chemotype (if necessary), source of origin (wild or cultivated), morphological group of the producing plant, and the name (definition) of the herbal pharmaceutical substance.
The "Structure" section for a herbal pharmaceutical substance obtained after grinding medicinal plant material includes an indication of its category (whole, ground, powder); for a herbal pharmaceutical substance obtained after processing medicinal plant material by various methods (extraction, distillation, pressing, fractionation, purification, concentration, fermentation, etc.), an indication of the aggregate (physical) state (e.g., dry, thick, liquid extract), as well as a description of components with a known therapeutic effect or markers (molecular formula, relative molecular weight, structural formula, including relative and absolute spatial structure, molecular formula and relative molecular weight) and other components.
The section on the manufacturer of medicinal herbal raw materials must contain the following information: the name, address, and responsibility of each supplier, each production site, or laboratory involved in the procurement (production) and quality control of the medicinal herbal raw materials.
The section on the manufacturer of a product made from medicinal herbal raw materials must contain the following information: the name, address, and responsibility of each supplier, each production site, or laboratory involved in the production and quality control of the product made from medicinal herbal raw materials.
The "Description of the Production Process and Its Control" section for medicinal herbal raw materials must contain information on the procurement process of wild-growing or cultivated medicinal herbal raw materials (geographical source of the medicinal plant, description of the cultivation process) and methods of further processing (collection, drying) and storage conditions. For a product made from medicinal herbal raw materials, information must be provided on the production process for obtaining the product, including a description of the processing, solvents and reagents, purification steps, and standardization (if necessary).
For the development of the production process, a summary must be provided describing the development of the herbal pharmaceutical substance. For the development of the production process for a product made from medicinal herbal raw materials, a summary must be provided describing the development of the product, taking into account the intended route of administration of the herbal medicinal product and its medical use. The results of a comparative phytochemical analysis of the medicinal herbal raw material and the product made from medicinal herbal raw materials must be considered, using bibliographic data (if necessary).
When describing the structure and other characteristics of medicinal plant materials, it is necessary to provide information on the botanical, macroscopic, microscopic, and phytochemical characteristics and biological activity (if necessary).
(as amended by Decision of the Council of the Eurasian Economic Commission dated May 22, 2023, No. 60)
When describing the composition and other characteristics of a product made from medicinal plant materials, it is necessary to provide information on the phyto- and physicochemical characteristics and biological activity of plant-based products (if necessary).
Specifications for medicinal plant materials and products made from medicinal plant materials should be provided (if necessary).
(as amended by Decision No. 60 of the Council of the Eurasian Economic Commission of May 22, 2023)
The analytical methods used for testing the herbal pharmaceutical substance must be specified, and reports on their validation (if they are not pharmacopoeial) must be provided, including experimental data for the analytical methods used for testing.
Batch analysis data must be presented as a description of the batches and the results of batch analysis for the herbal pharmaceutical substance, including such data for pharmacopoeial substances.
If necessary, a justification for the specifications of the herbal pharmaceutical substance must be provided.
(as amended by Decision No. 60 of the Council of the Eurasian Economic Commission of 22.05.2023)
Information on the reference materials and materials used for testing the herbal pharmaceutical substance must be provided.
If the monograph on the herbal pharmaceutical substance is included in the European Pharmacopoeia, the applicant may submit a certificate of conformity issued by the European Directorate for the Quality of Medicines (if available).
15.1.2. Herbal Medicinal Products.
Regarding the development of the formulation, a summary must be provided describing the development of the herbal medicinal product, taking into account the intended route of administration and use. Data on the phytochemical composition of the declared herbal medicinal product and data provided in bibliographic scientific sources must be analyzed. The "Description of the Manufacturing Process and Its Controls" section for a herbal medicinal product should contain information on the manufacturing process used to obtain the product, including a description of processing, solvents and reagents, excipients, purification steps, and standardization (if necessary).
15.1.3. Modules 4 and 5.
Results of preclinical (toxicological and pharmacological) and clinical studies.
For combination herbal medicinal products (including combinations with vitamins and/or minerals), if the individual components of the combination have not been adequately studied, data on each individual component of the combination must be provided.
(as amended by Decision of the Council of the Eurasian Economic Commission of 22.05.2023 No. 60)
15.2. Simplified Registration Dossier for Herbal Medicinal Products.
A simplified registration dossier for herbal medicinal products is submitted for herbal medicinal products in the dosage forms of tinctures, extracts, etc., as well as for crushed or powdered, cut-and-pressed parts of the plant, and other herbal medicinal products, subject to the following requirements:
the indications for use correspond to the generally known properties and composition of the medicinal plant and are intended for use without medical supervision for prophylactic or therapeutic purposes;
With the methods of administration and dosages specified by the general characteristics of the medicinal product;
intended for oral, external, topical, and/or inhalation use;
the safety of the herbal medicinal product is based on long-term experience (at least 10 years from the date of the first systematic and documented use of the herbal medicinal product in at least three Member States);
the labeling and instructions for medical use (package leaflet) of the herbal medicinal product must contain indications that:
the product is a herbal medicinal product for use for the stated purpose, based on experience of long-term use;
the consumer should consult a physician or qualified healthcare professional if symptoms persist or adverse reactions not listed in the instructions for medical use (package leaflet) are observed while using the herbal medicinal product. (as amended by Decision No. 60 of the Council of the Eurasian Economic Commission dated May 22, 2023)
If a herbal medicinal product contains vitamins or minerals, the simplified registration procedure is carried out provided that substantiated data are provided demonstrating that the action of the vitamins or minerals is complementary to the action of the herbal active ingredients in relation to the stated indications for use.
15.2.1. Module 2.
Bibliographic data or a conclusion from the specialist who prepared Sections 2.4 and 2.5 of the module stating that the herbal medicinal product in question or the corresponding product has been used for at least 10 years from the date of the first systematic and documented use of the herbal medicinal product in all Member States.
15.2.2. List of documents for the simplified registration dossier.
To confirm the pharmaceutical quality and consistency of the drug from batch to batch, the application is accompanied by a registration dossier consisting of modules 1–3 in accordance with Appendix No. 4 to the rules for the registration and examination of medicinal products for human use, approved by the Commission. Modules 4 and 5 of the registration dossier are compiled from copies of bibliographic sources and data underlying the specialist reviews in sections 2.4 and 2.5 of module 2 of the registration dossier.
16. Orphan drugs (drugs intended for the treatment of rare diseases)
For orphan drugs, the key provisions of Part II (registration in exceptional cases) may apply. The applicant must substantiate in the preclinical and clinical summaries the reasons why it is impossible to provide complete information and provide a justification for the benefit-risk balance of the orphan drugs in question.
(as amended by decisions of the Council of the Eurasian Economic Commission of January 30, 2020, No. 9, and March 17, 2022, No. 36)
IV. High-Tech Medicinal Products
of May 22, 2023, No. 60)
17.1. Introduction.
Registration dossiers for high-tech medicinal products must comply with the format requirements (modules 1-5 of the registration dossier) described in Part I of this Appendix. (as amended by Decision No. 60 of the Council of the Eurasian Economic Commission of 22 May 2023)
The technical requirements for Modules 3–5 shall apply to high-tech biological medicinal products, as described in Part I of this Appendix. The specific requirements for high-tech medicinal products, described in Sections 17.3, 17.4, and 17.5 of this Part, explain how the requirements of Part I of this Appendix apply to high-tech medicinal products.
(as amended by Decision No. 60 of the Council of the Eurasian Economic Commission of 22 May 2023)
Due to the specific nature of high-tech medicinal products, a risk-based approach may be used to determine the scope of necessary information and requirements for quality, preclinical, and clinical studies for their inclusion in the registration dossier in accordance with applicable Union guidelines or, in their absence, in accordance with Member State guidelines.
Risk analysis may encompass the entire development process. Risk factors that may be considered include: cell origin (autologous, allogeneic, xenogeneic), proliferative and/or differentiation capacity, ability to elicit an immune response, cell manipulation, combination of cells with bioactive molecules or medical devices, the nature of the gene therapy drug, the ability of viruses to replicate or microorganisms to multiply in vivo, the degree of integration of nucleic acid sequences or genes into the genome, duration of function (lifespan), risk of oncogenicity, and the route of administration or use.
Non-clinical and clinical data or experience with other related advanced medicinal products may also be considered in the risk analysis.
Any deviation from the requirements of this Appendix must be scientifically justified in Module 2 of the registration dossier. If a risk analysis is conducted, it must be described in Module 2 of the registration dossier. In this case, it is necessary to discuss the methodology used, the nature of the identified risks, and the impact of the results of the risk-based approach on the drug development and evaluation program. Any deviations from the requirements of this Appendix resulting from the risk analysis must also be described.
17.2. Definitions
High-tech medicinal products include the following types of medicinal products for medical use:
(paragraph introduced by Decision of the Council of the Eurasian Economic Commission dated 22.05.2023 No. 60)
gene therapy medicinal products;
medicines based on somatic cells;
tissue-engineered medicinal products (tissue-engineered products).
17.2.1. Gene therapy medicinal products.
A gene therapy medicinal product is a biological medicinal product:
containing an active substance containing or consisting of a recombinant nucleic acid, used or administered to humans for the purpose of regulating, repairing, replacing, adding, or removing a genetic sequence;
the therapeutic, prophylactic, or diagnostic effects of which are directly attributable to the recombinant nucleic acid sequence it contains, or to the genetic expression product of that sequence.
Gene therapy medicinal products do not include vaccines against infectious diseases.
17.2.2. Somatic Cell-Based Medicinal Products.
A somatic cell-based medicinal product (somatic cell therapy product) is a biological medicinal product containing (or consisting of) cells or tissues possessing the following characteristics:
subjected to significant manipulations that alter their biological characteristics, physiological functions, or structural properties significant for clinical use. The following are not considered such manipulations: cutting, grinding, shaping, centrifugation, treatment with antibiotic or antiseptic solutions, sterilization, irradiation, cell separation, concentration or purification, filtration, lyophilization, freezing, cryopreservation, or vitrification;
not intended for use to perform the same basic functions in the recipient and donor;
used in humans for the treatment, prevention, or diagnosis of a disease through the pharmacological, immunological, or metabolic action of the cells or tissues included in the medicinal product.
A high-tech medicinal product containing both autologous (originating from the patient) and allogeneic (coming from another person) cells or tissues should be considered a medicinal product intended for allogeneic use.
(paragraph introduced by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No. 36; as amended by Decision of the Council of the Eurasian Economic Commission dated 22.05.2023 No. 60)
A high-tech medicinal product that may fall under the definition of a tissue-engineered product and the definition of a somatic cell-based medicinal product shall be considered as a tissue-engineered medicinal product.
A high-tech medicinal product that may fall under the definition of a somatic cell-based medicinal product or the definition of a tissue-engineered product and a gene therapy medicinal product shall be considered as a gene therapy medicinal product.
(paragraph introduced by the decision of the Council of the Eurasian Economic Commission of 17.03.2022 N 36; as amended by the decision of the Council of the Eurasian Economic Commission of 22.05.2023 N 60)
17.2.3. Tissue-engineered drug (tissue-engineered drug).
A tissue-engineered medicinal product (tissue-engineered product) is a biological medicinal product containing engineered cells or tissues of human or animal origin, or consisting of such cells or tissues, intended for use in the regeneration, repair, or replacement of human tissue.
A tissue-engineered medicinal product may contain nonviable cells in addition to viable cells. Such a product may also contain additional substances (e.g., cellular products, biomolecules, biomaterials, chemicals, scaffolds, and matrices). Products containing nonviable cells and/or tissues of human or animal origin, or consisting solely of such cells and/or tissues, whose primary action is not a consequence of pharmacological, immunological, or metabolic action, are not tissue-engineered medicinal products. Cells or tissues are considered engineered if at least one of the following conditions is met:
the cells or tissues have undergone substantial manipulation to obtain biological characteristics, physiological functions, or structural properties relevant for regeneration, repair, or replacement. The types of manipulations specified in the third paragraph of section 17.2.2 shall not be considered substantial manipulation;
the cells or tissues are not intended to perform the same essential function(s) in the recipient as in the donor.
If a tissue-engineered medicinal product contains viable cells or tissues, the pharmacological, immunological, or metabolic action of such cells or tissues is considered the primary mechanism of action of the product.
A tissue-engineered medicinal product containing both autologous (derived from the patient) and allogeneic (derived from another person) cells or tissues is considered a medicinal product intended for allogeneic use.
If a high-tech medicinal product meets the definitions of both a tissue-engineered medicinal product and a somatic cell-based medicinal product, it must be classified as a tissue-engineered medicinal product.
If a high-tech medicinal product meets the definitions of both a gene therapy medicinal product and a somatic cell-based medicinal product or a tissue-engineered medicinal product, it must be classified as a gene therapy medicinal product.
(Section 17.2.3 introduced by Decision No. 60 of the Eurasian Economic Commission Council dated May 22, 2023)
17.3. Special Requirements for Module 3 of the Registration Dossier.
17.3.1. Special Requirements for All High-Tech Medicinal Products. (as amended by Decision No. 60 of the Council of the Eurasian Economic Commission dated May 22, 2023)
A description of the traceability system that the applicant undertakes to establish and maintain is required to trace the sources of acquisition (origin), production, packaging, storage, transportation, and delivery to the healthcare facility of an individual medicinal product and its starting materials and raw materials, including all substances that have come into contact with the cells or tissues contained therein.
The traceability system shall complement and be consistent with the requirements for Member State traceability systems for human cells and tissues.
17.3.2. Special requirements for gene therapy medicinal products.
17.3.2.1. Introduction: medicinal product, active substance, and starting materials.
17.3.2.1.1. Gene therapy medicinal products containing a recombinant nucleic acid sequence or a genetically modified microorganism or virus.
The medicinal product must consist of a nucleic acid sequence, a genetically modified microorganism, or a virus, and be packaged in primary packaging for medical use. The medicinal product may be combined with a medical device.
The active substance must consist of a nucleic acid sequence or a genetically modified microorganism or virus.
17.3.2.1.2. Gene therapy medicinal products containing genetically modified cells. The medicinal product must consist of genetically modified cells and be packaged in primary packaging for medical use. The medicinal product may be combined with a medical device.
The active substance must consist of cells genetically modified by one of the products specified in Section 17.3.2.1.1.
17.3.2.1.3. For products consisting of viruses or viral vectors, the starting materials are the components from which the viral vector is derived: the master seed bank of the viral or plasmid vector used to transfect recipient cells (packaging cells), and the master seed bank of the recipient cell line (packaging cell line).
17.3.2.1.4. For products consisting of plasmids, non-viral vectors, and genetically modified organisms other than viruses and viral vectors, the starting materials are the components used to obtain the producer cells: plasmids, bacterial host cells, and the recombinant microbial cell master bank.
17.3.2.1.5. For genetically modified cells, the starting materials are the components used to obtain the genetically modified cells, i.e., the vector starting materials, the vector, and human and animal cells. Good manufacturing practice principles should be applied from the vector banking system used for vector production to the finished product.
17.3.2.2. Special Requirements.
In addition to the requirements specified in Sections 3.2.1 and 3.2.2 of Part I of this Appendix, the following requirements should apply:
a) Information must be provided on all starting materials used for the production of the active substance, including products required for the genetic modification of human and animal cells and the subsequent cultivation and preservation of genetically modified cells (if necessary), taking into account the possible absence of purification steps;
b) For products containing microorganisms (including viruses), data must be provided on the genetic modification, sequencing, attenuation of microorganisms, tropism for specific tissue and cell types, dependence of microorganism properties on the cell cycle, pathogenicity, and characteristics of the parent strain;
c) Manufacturing and related impurities, and in particular contaminating agents in the form of replication-capable viruses, must be described in the relevant sections of the registration dossier if the vector is not replication-capable;
d) For plasmids, quantification of the various plasmid forms must be carried out throughout the shelf life of the product;
d) For genetically modified cells, testing of cell characteristics must be performed before and after genetic modification, as well as before and after any subsequent freezing (storage) procedure.
For genetically modified cells, in addition to the specific requirements for gene therapy medicinal products, the quality requirements for somatic cell-based medicinal products and tissue-engineered products in accordance with Section 17.3.3 of these Requirements should apply.
17.3.3. Special Requirements for Somatic Cell-Based Medicinal Products and Tissue-Engineered Products.
17.3.3.1. Introduction: Medicinal Product, Pharmaceutical Substance, and Starting Materials (Substances).
The medicinal product must consist of the pharmaceutical substance enclosed in the primary packaging for the proposed medical use and in its final combination, if it is a combination high-tech medicinal product.
The pharmaceutical substance must consist of engineered cells (tissues). Additional substances (e.g., scaffolds, matrices, articles, biomaterials, biomolecules, etc.) that are combined with processed cells to form a single unit are considered starting materials, even if they are not of biological origin.
Materials used in the production of the pharmaceutical substance (e.g., culture medium, growth factors) that are not intended to be included as a component of the pharmaceutical substance are considered raw materials.
17.3.3.2. Special Requirements.
In addition to the requirements specified in Sections 3.2.1 and 3.2.2 of Part I of this Appendix, the following requirements apply:
17.3.3.2.1. Starting Materials.
A summary of the acquisition, procurement, and testing of human tissues and cells used as starting materials must be provided. Justification must be provided if abnormal cells or tissues (e.g., cancer) were used as starting materials.
If allogeneic cell populations were pooled, the pooling strategy and measures to ensure traceability must be described. When validating the manufacturing process, characterizing the properties of the pharmaceutical substance and medicinal product, the analytical methods used in development, drawing up specifications and determining stability, it is necessary to take into account the potential variability due to the use of human or animal tissues and cells.
For xenogeneic cell-based medicinal products, information must be provided on the source of the animals (e.g., geographic origin, farm, age), specific acceptance criteria, measures to prevent and monitor infections in donor animals, animal testing for infectious agents, including vertically transmitted microorganisms and viruses, and confirmation of the suitability of animal welfare conditions.
For cell-based medicinal products derived from genetically modified animals, the special properties of the cells due to their genetic modification must be described. A detailed description of the method for creating and characterizing the properties of the transgenic animals must be provided.
For genetically modified cells, the requirements specified in Section 17.3.2 of this Appendix must also be taken into account.
The testing conditions of all additional substances (scaffolds, matrices, articles, biomaterials, biomolecules, etc.) combined with the engineered cells must be described and justified. For scaffolds, matrices, and articles falling within the definition of a medical device or an active implantable medical device, the information specified in Section 17.3.4 of this Appendix, as required for the evaluation of combination medicinal products for advanced therapy, must be provided.
17.3.3.2.2. Manufacturing Process
The manufacturing process must be validated to ensure batch and process homogeneity, the functional integrity of cells during production and transport (up to the point of use or administration), and the proper state of differentiation.
If cells are directly grown within or on a matrix, scaffold, or article, information must be provided on the validation of the cell culture process in terms of cell growth, function, and integrity of the combination.
17.3.3.2.3. Characterization and Quality Control Strategy.
Appropriate information must be provided to characterize the properties of the cell population or cell mixture in terms of identity, purity (e.g., presence of extraneous microbial agents or cellular contaminants), viability, potency, karyology, tumorigenicity, and suitability for the proposed medicinal use. The genetic stability of the cells must be confirmed.
Qualitative and, where possible, quantitative information must be provided on manufacturing and related impurities, as well as information on all materials that may lead to the formation of degradation products during manufacturing. The extent of impurity studies must be justified.
It must be justified that certain release quality control tests cannot be performed on the pharmaceutical substance or medicinal product, but can be performed on key intermediates and/or as part of in-process control.
If biologically active molecules (e.g., growth factors, cytokines) are components of cellular medicinal products, their effects and interactions with other components of the pharmaceutical substance must be described. If the three-dimensional structure is part of the intended function, the differentiation state, structural and functional organization of the cells, and the resulting extracellular matrix (if necessary) should be part of the description of the properties of such cellular medicinal products. Where necessary, descriptions of the physicochemical properties should be supplemented by preclinical studies.
17.3.3.2.4. Excipients.
For excipients used in somatotherapeutic medicinal products and tissue-engineered products (e.g., components of the transfer medium), the requirements for new excipients specified in Part I of this Appendix apply unless data on the interaction between cells or tissues and the excipients are available.
17.3.3.2.5. Development Studies.
When describing the development program, it is necessary to provide a rationale for the selection of materials and processes. In particular, it is necessary to analyze the integrity of the cell population in the finished medicinal product.
17.3.3.2.6. Standard Materials.
It is necessary to document and describe the properties of standard samples that are relevant and specific to the pharmaceutical substance and/or finished medicinal product.
17.3.4. Special Requirements for High-Tech Medicinal Products Containing Medical Devices. (as amended by Decision of the Council of the Eurasian Economic Commission dated 22.05.2023 No. 60)
17.3.4.1. High-Tech Medicinal Products Containing Medical Devices. (as amended by Decision of the Council of the Eurasian Economic Commission dated 22.05.2023 No. 60)
A description of the physical properties and action of the medicinal product, as well as a description of the methods used for its design, must be provided. It is necessary to describe the interaction and compatibility between genes and cells (tissues), on the one hand, and structural components, on the other.
17.3.4.2. Combined high-tech medicinal products. (as amended by Decision No. 60 of the Council of the Eurasian Economic Commission dated 22.05.2023)
A "combined high-tech medicinal product" is understood to mean a high-tech medicinal product that meets the following conditions:
it must include as a component of the product one or more medical devices, as defined by Union legislation on medical devices, or one or more active implantable medical devices, as defined by Union legislation on medical devices;
its cellular or tissue portion must contain viable cells or tissues;
its cellular or tissue portion, containing non-viable cells or tissues, must have the ability to exert an effect in the human body that can be considered primary in relation to the aforementioned devices.
The cellular or tissue portion of a high-tech combination medicinal product is subject to the special requirements for somatotherapeutic medicinal products and tissue-engineered products, as specified in Section 17.3.3 of this Appendix. If the cells have been genetically modified, the special requirements for gene therapy medicinal products, as specified in Section 17.3.2 of these Requirements, are applicable.
A medical device or active implantable medical device may be a component of a pharmaceutical substance. If a medical device or active implantable medical device is combined with cells during the manufacture, use, or administration of a medicinal product, it is considered a component of the finished medicinal product.
It is necessary to provide information concerning the medical device or active implantable medical device (which is a component of the pharmaceutical substance or medicinal product) necessary for the evaluation of high-tech combination medicinal products. Such information includes:
information on the selection and intended function of the medical device or implantable medical device and confirmation of the device's compatibility with other components of the product;
confirmation of the conformity of a medical device with the key requirements established by the Union legislation on medical devices, or the conformity of an active implantable device with the key requirements established by acts included in the Union law in the field of circulation of medical devices;
Confirmation of compliance of the medical device or implantable medical device with the requirements for spongiform encephalopathies (if necessary);
(as amended by Decision of the Council of the Eurasian Economic Commission dated 22.05.2023 No. 60)
The results of any assessment of the medical device or active implantable medical device by an authorized body (organization) in accordance with acts included in Union law on the circulation of medical devices (if necessary).
The notified person who conducted the assessment referred to in paragraph "d" of this section must, upon request of the authorized body conducting the examination of the application, provide all information related to the assessment results in accordance with acts included in Union law on the circulation of medical devices. This may include information and documents contained in the conformity assessment of the application under consideration for the purpose of examining the combined high-tech medicinal product as a whole (if necessary).
17.4. Special Requirements for Module 4 of the Registration Dossier.
17.4.1. Special Requirements for High-Tech Medicinal Products. (as amended by Decision No. 60 of the Council of the Eurasian Economic Commission dated May 22, 2023)
Due to the unique and diverse structural and biological properties of high-tech medicinal products, the requirements for Module 4 of the registration dossier specified in Section 4 of Part I of this Appendix are not always applicable to pharmacological and toxicological studies of medicinal products. The technical requirements of Sections 17.4.1 - 17.4.3 of this Appendix clarify how to fulfill the requirements of Part I of this Appendix for high-tech medicinal products. Where appropriate, taking into account the specific features of high-tech medicinal products, additional requirements are established for them.
The preclinical review must present the scientific rationale and analysis of the preclinical development and the criteria for selecting the relevant animal species and models (in vitro and in vivo). The selected animal models may include immunocompromised, knockout, humanized, or transgenic animals. The use of homologous models (e.g., mouse cell assays in mice) or disease-mimicking models should be considered, particularly for immunogenicity and immunotoxicity studies.
In addition to the requirements of Part I of this Appendix, data on the safety, suitability, and biocompatibility of all structural components (e.g., matrices, scaffolds, and devices) and any additional substances (e.g., cellular products, biomolecules, biomaterials, and chemicals) contained in the medicinal product should be provided. Their physical, mechanical, chemical, and biological properties should be considered.
17.4.2. Special Requirements for Gene Therapy Medicinal Products.
The design and type of gene therapy medicinal product should be considered when determining the extent and types of preclinical studies necessary to adequately characterize preclinical safety.
17.4.2.1. Pharmacology.
Results of in vitro and in vivo studies of effects relevant to the stated indication (i.e., pharmacodynamic studies of the mechanism of action) must be provided. These studies utilized appropriate animal models and species designed to confirm that the nucleic acid sequence reaches the target (organ or cells) and provides the desired function (expression level and functional activity). The duration of function of the nucleic acid sequence and the proposed dosing regimen in clinical trials must be described.
Target selectivity. If the gene therapy medicinal product is intended to exhibit selectivity or functionality limited to the target, results of studies confirming the specificity and duration of functionality and activity in target cells and tissues must be provided.
17.4.2.2. Pharmacokinetics.
Biodistribution studies must examine persistence, clearance, and mobilization. Additionally, they must address the risk of germline transfer.
If the registration dossier lacks a justification based on the type of medicinal product under consideration, results of dissemination and risk of transfer to third parties, as well as the results of an environmental risk assessment, must be provided.
17.4.2.3. Toxicology.
The toxicity of the finished gene therapy medicinal product must be studied. Additionally, depending on the type of medicinal product, separate testing of the pharmaceutical substance and excipients must be conducted, taking into account the in vivo effects of nucleic acid expression products not intended to evaluate their physiological function.
Single-dose toxicity studies may be combined with safety pharmacology and pharmacokinetic studies, for example, to study persistence. If repeated administration of the medicinal product to humans is anticipated, results of repeated-dose toxicity studies must be provided. The route and schedule of administration must be consistent with those used in clinical use. If a single administration may result in long-term functionality of the nucleic acid sequence in humans, repeated-dose toxicity studies may be necessary. Depending on the persistence of the gene therapy medicinal product and the anticipated potential risks, the duration of the studies may exceed standard toxicology studies. Justification for the duration of the studies must be provided.
Genotoxicity studies are required. However, standard genotoxicity studies are only necessary when testing a specific impurity or component of the delivery system.
Carcinogenicity studies are required. Standard lifelong carcinogenicity studies in rats are not required. However, depending on the type of medicinal product, tumorigenic potential should be studied in suitable in vivo or in vitro models.
Reproductive and developmental toxicity. If the registration dossier lacks adequate justification based on the type of medicinal product under consideration, results of fertility and general reproductive function studies must be provided. Results of embryofetal and perinatal toxicity studies, as well as germline transfer studies, must be provided.
Additional toxicology studies.
Integration studies. For all gene therapy medicinal products, results of integration studies must be provided unless the absence of such results is scientifically justified, for example, due to the lack of penetration of nucleic acid sequences into the cell nucleus. If biodistribution studies reveal a risk of germline transfer, integration studies must be conducted for gene therapy medicinal products suspected of not being capable of integration.
Immunogenicity and Immunotoxicity. Potential immunogenic and immunotoxic effects must be studied.
17.4.3. Special Requirements for Somatic Cell-Based Somatotherapeutic Medicinal Products and Tissue-Engineered Products.
17.4.3.1. Pharmacology.
To confirm the mechanism of action of a drug, appropriate primary pharmacology studies must be conducted. The interaction of cellular medicinal products with surrounding tissues must be studied.
The amount of drug required to achieve the desired effect (effective dose) and, depending on the type of drug, the dosage regimen must be determined.
To evaluate potential physiological effects unrelated to the therapeutic effect of a somatotherapeutic medicinal product, tissue engineering product, or adjuvant substances, secondary pharmacology studies must be provided, as biologically active molecules may be formed in addition to the required proteins, or the required proteins may have undesired targets.
17.4.3.2. Pharmacokinetics.
Standard pharmacokinetic studies to study absorption, distribution, metabolism, and excretion are not required. However, if the registration dossier does not adequately justify this based on the type of medicinal product under consideration, parameters such as viability, durability, distribution, growth, differentiation, and migration must be studied.
For somatotherapeutic medicinal products and tissue engineering products that continuously produce active biomolecules, the distribution, duration, and extent of expression of such molecules must be studied.
17.4.3.3. Toxicology.
The toxicity of the finished medicinal product must be studied. Separate studies of the pharmaceutical substance, excipients, additives, and all manufacturing impurities must be considered.
The duration of observations may exceed that required for standard toxicology studies; therefore, the expected life cycle of the medicinal product, as well as its pharmacodynamic and pharmacokinetic properties, must be taken into account. Justification for the duration of the studies must be provided.
Standard carcinogenicity and genotoxicity studies are not required, with the exception of the tumorigenic potential of the finished medicinal product.
The immunogenic and immunotoxic potential must be studied.
For cellular medicinal products containing animal cells, any associated safety issues, such as the risk of transmission of xenogenic pathogens to humans, must be studied.
17.5. Special Requirements for Module 5 of the Registration Dossier.
17.5.1. Special Requirements for High-Tech Medicinal Products. (as amended by Decision No. 60 of the Council of the Eurasian Economic Commission dated 22 May 2023)
17.5.1.1. The special requirements of this section are in addition to the requirements for Module 5 of the registration dossier of Section 5 of Part I of this Appendix.
17.5.1.2. If the clinical use of high-tech medicinal products requires special adjuvant therapy or surgical procedures, the entire range of therapeutic measures must be studied as a whole. Information on the standardization and optimization of such procedures during clinical development must be provided.
If medical devices used during surgical procedures for the application, implantation, or administration of a high-tech medicinal product may affect the efficacy and safety of that product, information on such devices must be provided.
A separate analysis must be provided to evaluate the application, implantation, administration, and subsequent monitoring. If necessary, a plan for training healthcare professionals in the procedures for use, application, implantation, and administration must be provided.
17.5.1.3. Given that the manufacturing process for advanced medicinal products may change during clinical development, additional studies may be required to confirm comparability.
17.5.1.4. During clinical development, risks associated with potential infectious agents or the use of material derived from animal sources must be examined and measures aimed at mitigating such risks must be described.
17.5.1.5. Dose-finding studies must be used to determine doses and dosing regimens.
17.5.1.6. Efficacy for the stated indications must be supported by relevant results from clinical trials that used endpoints that are clinically relevant to the intended use. Demonstration of long-term efficacy may be required for certain clinical conditions. A strategy for assessing long-term efficacy must be provided.
17.5.1.7. The risk management plan must include a strategy for long-term surveillance of safety and efficacy.
17.5.1.8. Safety and efficacy studies of combination medicinal products for advanced therapy must be planned and conducted on the entire combination product.
17.5.2. Special Requirements for Gene Therapy Medicinal Products.
17.5.2.1. Human Pharmacokinetic Studies.
Pharmacokinetic studies in humans should consider the following:
shedding studies aimed at investigating the excretion of gene therapy medicinal products;
biodistribution studies;
pharmacokinetic studies of the drug and gene expression products (e.g., expressed proteins or genomic signatures).
17.5.2.2. Human Pharmacodynamic Studies.
Pharmacodynamic studies should examine the expression and function of the nucleic acid sequence after administration of the gene therapy medicinal product.
17.5.2.3. Safety Studies.
Safety studies should consider the following:
emergence of replication-competent vectors;
emergence of new strains;
reassortment of existing genomic sequences;
tumor proliferation due to insertional mutagenesis.
17.5.3. Special Requirements for Somatic Cell-Based Medicinal Products.
17.5.3.1. Somatic Cell-Based Medicinal Products with a Mechanism of Action Based on the Production of Specific Active Biological Molecules.
If the mechanism of action of somatic therapeutic medicinal products is the production of a specific active biomolecule, the pharmacokinetic properties (in particular, the distribution, duration, and extent of expression) of such molecules must be described, if possible.
17.5.3.2. Biological Distribution, Persistence, and Long-Term Engraftment of Somatic Cell-Based Medicinal Product Components.
During clinical development, the biodistribution, persistence, and long-term engraftment of somatic therapeutic medicinal product components must be studied.
17.5.3.3. Safety Studies.
Safety studies must consider the following:
distribution and engraftment after administration;
ectopic engraftment;
oncogenic transformation and compliance with the properties of the relevant cell line (tissues).
17.5.4. Special Requirements for Tissue-Engineered Products.
17.5.4.1. Pharmacokinetic Studies.
If standard pharmacokinetic studies for tissue-engineered products are not relevant, the biodistribution, persistence, and degradation of their components must be studied during clinical development.
17.5.4.2. Pharmacodynamic Studies.
The design of pharmacodynamic studies should be based on the characteristics of the tissue-engineered product. Evidence of proof-of-concept and the kinetics of the product required to achieve the intended regeneration, repair, or replacement must be provided. Suitable pharmacodynamic markers related to the function and structure under consideration must be considered.
17.5.4.3. Safety Studies.
The safety studies of tissue-engineered products should be guided by the requirements specified in Section 17.5.3.3 of this Appendix.
dated April 23, 2021 No. 34, dated March 17, 2022 No. 36, dated May 22, 2023 No. 60)
II. APPLICATION
for re-registration of a medicinal product
Date of receipt of application
"__" _____________ 20__ г.
N __________________
Trade names of the medicinal product
Active pharmaceutical ingredients
Dosages or concentrations
Formulation
Dosage form
Marketing authorization holder
Applicant
Applicant's representative
Registration Certificate Details
Registration Certificate Number
Registration Date
Quality Regulatory Document Number
I guarantee the accuracy of and accept responsibility for the information contained in the submitted documents and data included in the registration dossier.
I agree that if the documents and data required to complete the registration dossier are not submitted within 30 days, this application will be rejected based on comments from the authorized body (expert organization) of the reference state.
I confirm that all data in the registration dossier was obtained in accordance with the established procedure and does not violate the intellectual property rights of third parties (subparagraphs 5.3 and 5.4 of the Appendix to this application).
I also confirm that all required fees (duties) have been paid (will be paid) in accordance with legal requirements.
A power of attorney for legally significant actions on behalf of the registration certificate holder is attached (subparagraph 5.1 of the Appendix to this application).
On behalf of the applicant
_______________________________
(Signature)
(Name, Surname)
(Position)
Stamp
1. General Application Points
1.1. This application is submitted in accordance with the following:
1.1.1. The application is submitted under the mutual recognition procedure:
Reference State
Trade name in the reference state
Registration date
Registration certificate number
Copy of the registration certificate
Application identification number
Other Eurasian Economic Union member states for filing an application (if any)
Trade names in recognition states (if the trade name differs from the one registered in the reference state)
1.1.2. The application was submitted through a decentralized procedure:
Trade name in the reference State
Recognition States for filing the application
Trade names in recognition States (if trade names differ from the reference State)
Note: This section must be completed for any application, including applications referenced in this section.
2. Approved or pending amendments since the issuance of the marketing authorization
N
Submission date
Change approval date
Change type (procedure type), brief description of the change
...
If an application is submitted for the type of medicinal product listed below, the remaining sections of the application relating to other types of medicinal products do not need to be completed.
ORIGINAL MEDICINAL PRODUCT
biological drug
another drug
New active pharmaceutical ingredient (hereinafter referred to as API)
Note: There is no information on the API in the unified register of registered medicines of the Eurasian Economic Union or in the corresponding national registries of the Eurasian Economic Union member states.
Known API
Note: There is information on the API in the unified register of registered medicines of the Eurasian Economic Union or in the corresponding national registries of the Eurasian Economic Union member states.
GENERIC DRUG
one-component
multicomponent
Original medicinal product:
name of medicinal product, dosage, dosage form
marketing certificate holder (company in whose name the marketing authorization is issued), registration date, marketing authorization number, Eurasian Economic Union member states where the original medicinal product is registered
Reference medicinal product used in equivalence studies (if any):
name of medicinal product, strength, dosage form
marketing authorization holder (company in whose name the marketing authorization is issued), registration date, marketing authorization number, Eurasian Economic Union member states where the reference medicinal product is registered
provide justification for the use of the reference medicinal product if it differs from the original medicinal product
availability of recommendations from the Expert Committee on Medicines on the selection of the reference medicinal product
Note: This section must be completed for each medicinal product used in equivalence studies.
BIO-SIMILAR DRUG (BIOANALOGUE)
Original biological medicinal product:
Name of the medicinal product, dosage, formulation
Marketing Authorization Holder (company in whose name the registration certificate is issued), registration date, registration certificate number, Eurasian Economic Union member states where the original medicinal product is registered
Reference biological medicinal product:
Marketing Authorization Holder, registration date, registration certificate number, Member States of the Union where the reference medicinal product is registered
Availability of recommendations from the Expert Committee on Medicinal Products on the selection of the reference medicinal product
Differences compared to the reference biological medicinal product (if any):
Differences in source materials
Differences in the manufacturing process
Different indications for use
Differences in dosage form
Different dosages (quantitative changes in the API)
Different route of administration
Other differences:________________________
HYBRID DRUG
marketing certificate holder, registration date, marketing authorization number, EU member states where the original medicinal product is registered
Differences compared to the original medicinal product:
Changes in the active pharmaceutical ingredient
Different dosage form
Different dosages (quantitative changes in the active pharmaceutical ingredient)
Different pharmacokinetics (including different bioavailability);
Different indication for use
Other differences: ______________
COMBINATION DRUG
a well-known combination
new combination
Original medicinal product (in case of a known combination):
Name of the medicinal product, dosage, dosage form
Marketing Authorization Holder, registration date, registration certificate number, Eurasian Economic Union member states where the original medicinal product is registered
A MEDICINAL PRODUCT WITH WELL-RESEARCHED MEDICAL USE
RADIOPHARMACEUTICAL DRUG OR PRECURSOR
radiopharmaceutical kit
radionuclide precursor
radionuclide source (primary and secondary) (if available)
generator
HOMEOPATHIC MEDICINE
a new homeopathic drug not included in pharmacopoeias and monographs
homeopathic preparation included in pharmacopoeias and monographs
HERBAL MEDICINE
ORPHAN DRUG
Has the medicinal product been granted orphan drug status in the Eurasian Economic Union member states or outside of it?
no
in consideration
yes
date
registration certificate number of the orphan medicinal product
member states of the Eurasian Economic Union and/or other states that have assigned orphan medicinal product status to this medicinal product
Orphan drug designation denied:
Date
Decision number
Application for orphan drug designation withdrawn
Copy of the document confirming the assignment of orphan drug designation to the medicinal product (if any) (Subclause 5.2 of the Appendix to this application).
MEDICINAL PRODUCT SUBMITTED FOR REGISTRATION
IN ACCORDANCE WITH SECTION VII OF THE RULES
If a medicinal product is submitted for re-registration in accordance with Section VII of the Rules, it is necessary to indicate the type of procedure under which it was registered:
registration of a medicinal product in exceptional cases
conditional registration of a medicinal product
Did the regulatory authority impose any special obligations or post-registration measures as conditions of registration of the medicinal product?
Special obligations or post-registration measures as conditions of registration:
Restrictions on the use of a medicinal product established during the registration of a medicinal product
Obligations of the registration certificate holder to be fulfilled within the framework of registration
Deadlines for fulfilling obligations and imposed restrictions for the registration certificate holder established during the registration of a medicinal product
Status of fulfillment of obligations by the registration certificate holder
3. Special points of the application
3.1. Name and ATX code
3.1.1. Name of the medicinal product
3.1.2. Name of the API or composition
Note. Only one name should be given in the following order: international nonproprietary name (hereinafter referred to as INN) <*>, name according to the Pharmacopoeia of the Eurasian Economic Union, pharmacopoeias of the member states (or main pharmacopoeias in accordance with the Concept of Harmonization of Pharmacopoeia of the Member States of the Eurasian Economic Union, approved by the Eurasian Economic Commission), common or group name, scientific (chemical) name.
--------------------------------
<*> The name of the API must be indicated according to its recommended INN, with an indication of its salts or hydrate form, if necessary.
3.1.3. Pharmacotherapeutic group (use current ATC code)
ATC code
Group
If an ATC code has not been assigned, please indicate whether an application for an ATC code has been submitted.
3.2. Dosage, dosage form, and packaging, route of administration, capacity of primary packaging, number of dosage units per packaging.
3.2.1. Dosage and dosage form
(Use the list of standard terms of the nomenclature of dosage forms used in the Eurasian Economic Union.)
Dosage or concentration
3.2.2. Route of administration (use the list of standard terms for the nomenclature of dosage forms)
3.2.3. Packaging: primary and secondary packaging, intermediate packaging (if any), closure system and delivery devices, including a description of the material from which they are made (use the list of standard terms for the nomenclature of dosage forms), packaging of bulk products (if any)
For each type of packaging, please indicate:
3.2.3.1. Number of dosage units per packaging
3.2.3.2. Proposed shelf life
3.2.3.3. Proposed shelf life (after first opening of primary or intermediate packaging)
3.2.3.4. Proposed shelf life (after reconstitution (dissolution) or dilution)
3.2.3.5. Proposed storage conditions
3.2.3.6. Proposed storage conditions after first opening of packaging (primary or intermediate)
3.2.4. Information on administration devices
3.3. Dispensing category
by prescription
3.3.1. Suggested dispencing category:
without a prescription
in a hospital setting
3.4. Marketing Authorization Holder
3.4.1. Marketing Authorization Holder:
Legal entity name,
legal address
country
telephone and fax numbers (if available)
email address
3.4.2. Representative of the registration certificate holder (person acting on behalf of the registration certificate holder - applicant):
Name of the legal entity or last name, first name, and patronymic of an individual
When completing this section, please attach a power of attorney to perform legally significant actions on behalf of the marketing authorization holder (subparagraph 5.1 of the appendix to this application).
3.4.3. The applicant's representative (the person acting on behalf of the applicant) after registration of the medicinal product, if different from those specified in subparagraph 3.4.2 of this application:
Last name, first name, and patronymic of the applicant's representative or name of the legal entity
Legal address of the legal entity
State
Telephone and fax numbers (if available)
Email address
When completing this section, please attach a power of attorney (subsection 5.1 of the appendix to this application).
3.4.4. Authorized representative of the marketing authorization holder responsible for pharmacovigilance:
Last name and first name of the authorized representative of the marketing authorization holder responsible for pharmacovigilance
Name of the legal entity (marketing authorization holder)
Legal address of the legal entity (marketing authorization holder)
24-hour telephone and fax numbers
Please indicate the place of registration and actual place of residence of the authorized person of the registration certificate holder responsible for pharmacovigilance.
Pharmacovigilance Master File:
Number:
Location Address:
3.4.5. The authorized person of the registration certificate holder in a member state of the Eurasian Economic Union for the implementation of pharmacovigilance, if it differs from that specified in subparagraph 3.4.4 of this application:
Last name, first name, and patronymic of the authorized representative of the marketing authorization holder responsible for pharmacovigilance
Address of the legal entity
Country
24-hour telephone (fax)
Email
Please indicate the registered address, actual place of residence, and telephone number of the authorized person in the Eurasian Economic Union member state responsible for pharmacovigilance.
3.5. Manufacturer of the medicinal product
3.5.1. The manufacturer responsible for batch release quality control of the medicinal product (as specified in the general characteristics of the medicinal product, package insert, and, if applicable, labeling).
Name of the legal entity
Address of the place of business
3.5.2. Laboratory of the manufacturing country responsible for quality control of blood products and vaccines, responsible for batch quality control (release)
Laboratory name
Address of location
3.5.3. Organization responsible for handling complaints within the Eurasian Economic Union (for each member state, if any)
Name of legal entity
Location of legal entity
3.5.4. Manufacturer of the medicinal product and manufacturing sites:
All manufacturing sites involved in the medicinal product manufacturing process (including solvents), indicating the manufacturing stage.
Name of the manufacturing stage <*>, name of the legal entity <*>
Address of the place of business <*>
State <*>
Telephone and fax numbers (if available) <*>
Email address <*>
<*> The specified fields must be completed for each stage of the production process (please attach a diagram showing the sequence and actions for the various production sites involved in the production process, including final inspection).
Was the site inspected for compliance with the Good Manufacturing Practice Rules of the Eurasian Economic Union, approved by the Eurasian Economic Commission, by an authorized body (organization) of a Eurasian Economic Union member state?
If yes, please indicate:
date of last inspection
name of the authorized body that conducted the inspection
type of inspection
category of medicinal products and APIs inspected
conclusion
complies: no
Was the site inspected for compliance with good manufacturing practice requirements by an authorized body (organization) of another state:
3.5.5. API Manufacturer and Manufacturing Sites
All manufacturing sites involved in the production of each API, indicating the manufacturing stage. For biological medicinal products, all sites storing the master and working cell banks, as well as sites preparing the working cell bank, must be listed.
Name of the manufacturing process stage, active pharmaceutical ingredient
Name of the legal entity, last name, first name, and patronymic of the individual entrepreneur
For each API, please attach a statement from the manufacturer's authorized representative in accordance with subparagraph 5.5 of the appendix to this application (please attach a diagram showing the sequence and actions for the various production sites involved in the manufacturing process, including final inspection).
Was the site inspected for compliance with the Good Manufacturing Practice requirements of the Eurasian Economic Union by the authorized body of the Eurasian Economic Union member state?
Выдан ли сертификат соответствия монографии Европейской фармакопеи для АФС:
дyes
If Yes:
Name of the active pharmaceutical ingredient
Name of the legal entity or the last name, first name, and patronymic of the individual entrepreneur (manufacturer)
Compliance document number
Date of last revision
Date of last inspection
Name of the authorized body that conducted the inspection
Type of inspection
Conclusion
Will the API manufacturer's master file be used as part of the registration dossier?
If yes:
Name of the API manufacturer's master file holder
Name of the API manufacturer, if different from the holder of the API manufacturer's master file
Has a certificate for the vaccine antigen master file (hereinafter referred to as VAMF) used in the registration dossier been issued or has an application been submitted for its receipt?
Name of the vaccine antigen
Name of the vaccine antigen manufacturer (certificate holder for the MVFA)
Application (certificate) number
Submission date (if under review)
Approval or last revision date (if any)
3.5.6. Contract research organizations (CROs) involved in clinical trials to determine bioavailability and/or bioequivalence, or that were involved in validating blood product manufacturing processes.
For each CRO, indicate where the analytical testing was performed and clinical data were collected, as well as:
Study title
Protocol code
EudraCT number (if available)
ClinicalTrials.gov number (if available)
Name of contract research organization
Contract research organization address
Phone and fax numbers (if available)
3.6. Qualitative and quantitative composition of the medicinal product.
3.6.1. Qualitative and quantitative composition of the medicinal product (API and excipients)
The composition unit must be specified (per dosage unit, per unit volume, per unit mass, etc.).
List the API separately from the excipients:
Name of API <*>
Quantity (in units of mass, volume, activity, or concentration, etc.)
Unit of measurement
Article (monograph)
Name of excipients
Quantity (in units of mass, volume, activity, or concentration, etc.
Note. <*> Only one name for each API must be specified in the following order: INN, name according to the Eurasian Economic Union Pharmacopoeia, name according to the pharmacopoeias of the Eurasian Economic Union member states (or the main pharmacopoeias in accordance with the Concept of Harmonization of Pharmacopoeia of the Eurasian Economic Union Member States), common or generic name, and scientific (chemical) name.
<**> The name of the API must be specified according to its INN recommended by the World Health Organization, with an indication of its salts or hydrated form, if necessary.
Excess information should not be included in the composition columns; it must be presented below:
active pharmaceutical ingredients
excipient(s)
3.6.2. List of materials of animal and (or) human origin included in the composition of the medicinal product or used in the process of its production
absent
Name
Function
From animals susceptible to GE <3>
Other animals
Of human origin
Certificate of conformity with the European Pharmacopoeia regarding GE <3> (indicate the number)
АФС
ВВ <1>
Р <2>
1
2
3
....
Indicate the availability of a certificate of conformity with the European Pharmacopoeia regarding GE <3> or a document issued by the authorized veterinary supervision bodies of the country of origin of raw materials regarding the registration in the country (based on the results of clinical and laboratory monitoring) of cases of GE <3>
<1> ES - excipient (including starting materials used in the production of the API/excipient).
<2> R - reagent/culture medium (including those used to prepare the master and working cell banks).
<3> GE - spongiform encephalopathy.
3.6.3. Has a certificate for the plasma master file (hereinafter referred to as the PMF) used in this dossier been issued, or has an application for one been submitted?
Substance (material) with a reference to the IFP
API
ES<1>
R<2>
Name of the owner (applicant for the IFP)
Certificate (application) number
Application submission date (if under review)
Approval or last review date (if a certificate exists)
<1> ES - excipient (including starting materials used in the production of the API (excipient)).
<2> R - reagent (culture medium) (including those used to prepare the master and working cell banks).
3.6.4. Does the medicinal product contain or consist of genetically modified organisms (GMOs):
If yes, does the drug meet the established requirements?:
Make the necessary link.
4. Other information
4.1. Are intellectual property rights to a medicinal product protected by patents valid in the territory of a member state of the Eurasian Economic Union?
If yes, please provide the following information:
Patent number
Valid in the territory of the Member State
Issue date
Valid until
Patent owner
To register medicinal products based on or related to intellectual property rights granted under the laws of a Eurasian Economic Union member state, the applicant must submit a certified copy of a valid patent in the Eurasian Economic Union member state or a license agreement granting the right to manufacture and sell the registered medicinal product. Applicants must submit a letter stating that the intellectual property rights of third parties, protected by the patent or licensed, are not infringed by the registration of the medicinal product.
4.2. Is the trademark registered in the Eurasian Economic Union member states?
If yes, please provide such information:
Attach a certified copy of the trademark registration certificate valid in the territory of a Eurasian Economic Union member state, certified by the applicant.
If the applicant is not the copyright holder, attach a certified copy of the license agreement or confirmation of registration of the right to use the trademark.
4.3. Is the medicinal product registered in the country of manufacture?
Is the medicinal product registered in other countries?
4.4. Has a preliminary scientific consultation been conducted regarding this medicinal product in the member states of the Eurasian Economic Union?
Eurasian Economic Union member state
date of the event
notation of the presence of the conclusion in the dossier
Has a prior scientific consultation been conducted regarding this medicinal product in the Expert Committee on Medicines:
date of the conclusion
note of the presence of the conclusion in the dossier
4.5. Information on refusals, revocations, and suspensions of registration certificates for medicinal products in the country of manufacture and other countries.
Type of restriction
Reason
Period
5. Application attachments
(submitted on paper or as electronic documents
signed (certified) with an electronic signature)
5.1. A power of attorney to perform legally significant actions on behalf of the marketing authorization holder and the applicant (if applicable).
5.2. A copy of the document confirming the orphan status of the medicinal product.
5.3. Copies of valid patents in the member states of the Eurasian Economic Union in relation to the medicinal product being registered.
5.4. Written confirmation from the applicant that the registration of the medicinal product does not infringe the intellectual property rights of third parties.
5.5. A copy of the trademark registration certificate valid in the territory of the member state of the Eurasian Economic Union.
5.6. A statement from the authorized person for quality control on the compliance of production with the rules of good manufacturing practice of the Eurasian Economic Union and good practice guidelines for starting materials for each manufacturing site used in the production of the medicinal product and API, including sites where quality control is performed (in-process control).
III. APPLICATION
on amendments to the registration dossier
of a medicinal product
Appendix No. 3
INSTRUCTIONS FOR DRAWING UP A QUALITY
REGULATORY DOCUMENT ACCOMPANIING
AN APPLICATION FOR REGISTRATION OF A DRUG
The draft regulatory documentation on quality control (hereinafter referred to as RD) must include 8 sections:
1. Title page, including:
name of the medicinal product (trade name and INN, or, if none, the common (general) name; if none, the chemical name);
strength(s);
name of the marketing authorization holder and country;
field for indicating the regulatory document number (indicated as the registration certificate number issued by the reference state and the registration date in the format DD.MM.YYYY, indicated with a hyphen);
approval stamp.
2. The composition of the medicinal product is provided in accordance with Section 3.2.P.5.1 of Module 3 of the registration dossier (without specifying the functional purpose) in a separate section of the regulatory document. This section specifies the qualitative and quantitative composition of the pharmaceutical substances and excipients, with references to pharmacopoeias or regulatory documents governing their quality. 3. Specification (in accordance with Section 3.2.P.5.1 of Module 3 of the registration dossier) in the form of a 3-column table:
list of all quality parameters;
standards (acceptable limits);
references to test methods.
Quality parameters should be established in accordance with the requirements of the general pharmacopoeia monographs of the Pharmacopoeia of the Eurasian Economic Union (hereinafter referred to as the Union) for dosage forms, taking into account the specific features of the specific dosage form of the medicinal product, depending on the nature of the pharmaceutical substance, and in accordance with this document.
The names of the quality parameters in the specification are indicated in accordance with the Pharmacopoeia of the Eurasian Economic Union.
If testing of individual parameters is conducted randomly or at a specified frequency, the specification shall establish the randomness and frequency of testing. 4. A detailed description of the implementation of the methods and techniques for testing the medicinal product for all quality parameters of the specification, with references to the Pharmacopoeia of the Union (if applicable), is provided in accordance with Section 3.2.P.5.2 of Module 3 of the registration dossier.
5. The "Packaging" section of the ND describes the primary packaging (ampoules, vials, jars, bags, etc.), the number of units in the primary packaging (e.g., the number of tablets in a blister pack or cell-less package), intermediate packaging, secondary (consumer) packaging, and the number of primary packages within it (e.g., the number of blister packs in the secondary packaging), the presence of a desiccant, a package insert (instructions for medical use), completeness (needle, dropper, clamp, etc.), etc.
6. The "Labeling" section of the ND refers to Section 1.3.2 of Module 1 of the registration dossier.
7. Storage conditions.
8. Expiry date (storage period).
Appendix No. 4
FOR THE FORMAT AND LOCATION OF DOCUMENTS IN THE REGISTRATION DOSSIER
OF A DRUG IN THE FORMAT OF A GENERAL
TECHNICAL DOCUMENT (GTD)
I. List of documents in the modules of the registration dossier
NAME OF DOCUMENTS
MODULE 1. ADMINISTRATIVE INFORMATION
1.0. Covering Letter (as in the CTD)
1.1. Contents
1.2.1. Application for registration of a medicinal product
1.2.2. Documents confirming payment for expert evaluation and/or registration fee (duty) in the cases and according to the procedure established by the legislation of the Eurasian Economic Union member state conducting the registration <*>
1.2.3. A copy of the medicinal product certificate, in the format recommended by the WHO, issued by the authorized body of the manufacturing country. If such a certificate is not available, a document confirming registration in the manufacturing country and/or in the country holding the marketing authorization for the medicinal product (if any) is submitted.
1.2.4 A translation into Russian and a duly certified copy of the expert report issued by the authorized body upon registration of the medicinal product in the country of manufacture or in the country holding the registration certificate (if any).
As part of the procedure for bringing the registration dossier of a medicinal product registered under the national procedure in the member states of the Eurasian Economic Union into compliance with the Rules for Registration and Expertise of Medicinal Products for Medical Use, approved by Decision No. 78 of the Council of the Eurasian Economic Commission dated 3 November 2016 (hereinafter referred to as "bringing it into compliance with Union requirements"), the submission of information is not mandatory.
1.2.5. Conclusion (recommendation) of the authorized body (authorized organization) of a member state of the Eurasian Economic Union based on the results of a preliminary scientific consultation regarding this medicinal product in the member state of the Eurasian Economic Union (if any)
1.2.6. Recommendation of the Expert Committee on Medicines based on the results of a preliminary scientific consultation regarding this medicinal product, including a conclusion on the rationality of the combination of active ingredients of the combined medicinal product (if any)
(clause 1.2.6 as amended by Decision of the Council of the Eurasian Economic Commission dated 22.05.2023 N 60)
1.3. General characteristics of the medicinal product, instructions for medical use (package leaflet), labeling:
1.3.1. Draft general characteristics of the medicinal product, instructions for medical use (package leaflet), compiled in accordance with the requirements of acts of the bodies of the Eurasian Economic Union in Russian
1.3.2. Mock-ups of primary (internal) and secondary (consumer) packaging, as well as intermediate packaging, prepared in accordance with the requirements of the Eurasian Economic Union's governing bodies. Mock-ups of intermediate packaging, labels, and stickers are submitted if available.
(as amended by Decision of the Council of the Eurasian Economic Commission dated September 23, 2022, No. 141)
1.3.3. Results of user testing of the IMP mock-up (in cases specified in Appendix No. 12 to the requirements for the instructions for medical use of a medicinal product and the general characteristics of the medicinal product for medical use, approved by Decision of the Council of the Eurasian Economic Commission dated November 3, 2016, No. 88)
(clause 1.3.3 as amended by Decision of the Council of the Eurasian Economic Commission dated October 20, 2023, No. 114)
1.3.4. Copies of the general characteristics of the medicinal product, certified by the marketing authorization holder, with the date of the last revision, and the instructions for medical use (package leaflet), approved by the authorized body of the manufacturing country and/or the marketing authorization holder country and/or another country with a well-regulated pharmaceutical market where the medicinal product is registered (if any)
1.4. Information on the regulatory status of the medicinal product in other countries (if any)
1.4.1. A list of countries in which the medicinal product has been submitted for registration, registered, has been denied registration, or its circulation on the market in these countries has been suspended, indicating the name of the medicinal product, the number and date of the marketing authorization, its validity period, or the date of the decision to refuse registration or suspend the marketing authorization. The information provided must be certified by the marketing authorization holder.
1.5. Quality documents:
1.5.1. a certificate of conformity with the article of the Pharmacopoeia of the Eurasian Economic Union or the European Pharmacopoeia on spongiform encephalopathy or a document issued by the authorized veterinary supervision bodies of the country of origin of the raw materials in the case of using pharmaceutical substances of animal origin (if applicable)
1.5.2. A letter from the active substance master file holder, signed by the responsible person of the active substance master file holder (or a copy of such a letter), containing an obligation to notify the manufacturer of the medicinal product and the competent authority of the Member State of any changes before any significant changes are made to the active substance master file, as well as a translation of such letter, certified by the marketing authorization holder or notarized.
(Clause 1.5.2 as amended by Decision No. 60 of the Council of the Eurasian Economic Commission dated May 22, 2023)
1.5.3. A letter confirming the consent of the pharmaceutical substance master file holder to submit documents from the closed section of the pharmaceutical substance master file upon request of the authorized body of a member state of the Eurasian Economic Union.
1.5.4. A copy of the certificate of conformity of the pharmaceutical substance with the requirements of the European Pharmacopoeia (if any).
1.5.5. A copy of the plasma master file certificate issued by the authorized body of the manufacturing country (if any).
1.5.6. A copy of the vaccine antigen master file certificate issued by the authorized body of the manufacturing country (if any).
1.5.7. A draft regulatory document on quality, prepared in accordance with the Guidelines for the preparation of a regulatory document on the quality of a medicinal product, approved by Decision No. 151 of the Board of the Eurasian Economic Commission dated September 7, 2018. (clause 1.5.7 introduced by the decision of the Council of the Eurasian Economic Commission dated 30.01.2020 N 9)
1.6. Production documents:
1.6.1. information on the date of submission and the registration number in the relevant register of a member state of the Eurasian Economic Union or a copy of a valid document confirming the compliance of the manufacturer (the manufacturing site that manufactures the finished dosage form and carries out quality control) of the medicinal product applied for registration with the requirements of the Rules of Good Manufacturing Practice of the Eurasian Economic Union approved by the Decision of the Council of the Eurasian Economic Commission dated November 3, 2016 N 77 (hereinafter referred to as the Rules of Good Manufacturing Practice of the Union) and issued by the authorized body of the member state of the Eurasian Economic Union (if applicable in accordance with paragraph 29 of the Rules for Registration and Expertise of Medicines for Medical Use), as well as copies of valid documents confirming the compliance of the manufacturer's manufacturing site with the requirements of good manufacturing practice and issued by the authorized bodies of the country (countries) in which the manufacturing site (production sites) that manufactures the finished dosage form and carries out quality control is located, and (or) another authorized body, and the address of the website of the register of certificates of conformity with the requirements of good manufacturing practice issued by the authorized body Manufacturing practices (e.g., EudraGMP) on the Internet (if available) (if applicable in accordance with paragraph 29 of the Rules for the Registration and Examination of Medicinal Products for Human Use)
(paragraph 1.6.1 as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated October 20, 2023)
1.6.2. Copies of the current permit (license) for the manufacture of medicinal products (with appendices) issued by the authorized body of the country in which the manufacturing site(s) producing the finished dosage form and performing release quality control are located. For manufacturing sites located in the territories of member states of the Eurasian Economic Union, instead of the specified documents, information on the date of submission and the registration number of the license (permit) for the production of medicinal products issued by the authorized body of the member state of the Eurasian Economic Union in the relevant register may be submitted.
(Clause 1.6.2 as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated October 20, 2023)
1.6.3. a copy of the report (copies of reports) on the inspection of the manufacturing site (manufacturing sites producing the finished dosage form and final quality control) for compliance with GMP, carried out by the authorized body of the manufacturing country or another authorized body within the last 3 years, as well as a plan and report on the implementation of corrective and preventive actions (CAPA) after the inspection (if any), and in cases stipulated by paragraph 30 of the Rules for the Registration and Examination of Medicinal Products for Human Use, the address of the website of the authorized body on the Internet containing information from the GMP inspection database (e.g. EudraGMP). When submitting documents in accordance with paragraph 1.6.1 of these Requirements, as well as within the framework of the procedure for bringing them into compliance with the requirements of the Union, the submission of information is not mandatory
(Clause 1.6.3 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
1.6.4 - 1.6.5. Repealed effective 20 December 2023. - Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114
1.6.6. Information on any regulatory measures taken by the authorized body that carried out inspections over the past three years based on the inspection results (from the date of application) in relation to the declared production site (if any). When submitting documents in accordance with Clause 1.6.1 of these Requirements and as part of the procedure for bringing them into compliance with Union requirements, the submission of information is optional.
1.6.7. A letter from the authorized quality representative confirming that the manufacturing conditions of the medicinal product submitted for registration comply with the requirements of the Good Manufacturing Practice Rules of the Eurasian Economic Union, approved by the Eurasian Economic Commission, including with respect to starting materials for each manufacturing site used in the manufacturing of the medicinal product and active pharmaceutical ingredient, including sites where quality control and in-process control are performed. The letter must be signed by the authorized quality representative and certified by the manufacturer's seal (stamp), if necessary, with a Russian translation.
1.6.8. Information on complaints regarding the quality of medicinal products manufactured at the manufacturing site of the medicinal product submitted for registration over the past three years (if applicable). When submitting documents in accordance with paragraph 1.6.1 of these Requirements and as part of the procedure for bringing the product into compliance with Union requirements, the submission of information is optional.
1.6.9. Consent to conduct a pharmaceutical inspection for compliance with the requirements of international treaties and acts constituting Union law
(clause 1.6.9 as amended by Decision No. 9 of the Council of the Eurasian Economic Commission dated 30.01.2020)
1.6.10. Repealed effective 20 December 2023. - Decision No. 114 of the Council of the Eurasian Economic Commission dated 20.10.2023
(clause 1.7.1 as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated 20.10.2023)
1.7.2. Information about the specialist who prepared the preclinical study summary (if any). Submission of this information is not mandatory for the purposes of aligning with Union requirements.
(Section 1.7.2 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
1.7.3. Information about the specialist who prepared the clinical study summary (if any). Submission of this information is not mandatory for the purposes of aligning with Union requirements.
(Section 1.7.3 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
1.8.1. A letter from the marketing authorization holder containing information on the additional trade name of the medicinal product (if applicable). Submission of this information is not mandatory for the purposes of aligning with Union requirements.
(Clause 1.8.1 as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated 20.10.2023)
1.8.2. Clinical trial documents and a summary to support the registration application (if applicable)
(as amended by Decision No. 14 of the Council of the Eurasian Economic Commission dated 05.03.2021)
1.8.2.1. Permission from the authorized body to conduct the clinical trial in the member states of the Eurasian Economic Union, including permission to amend the registration dossier (if any). Submission of information is not mandatory as part of the procedure for bringing the clinical trial into compliance with Union requirements.
(Clause 1.8.2.1 as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated 20.10.2023)
1.8.2.2. List of inspections conducted for compliance with the Rules of Good Clinical Practice of the Eurasian Economic Union (submission of information is not mandatory as part of the procedure for bringing it into compliance with Union requirements)
(clause 1.8.2.2 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
1.8.2.3 - 1.8.2.4. Repealed effective 20 December 2023. - Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114
1.8.2.5. Summary of an application for registration of a medicinal product with well-studied medical use (submission of information is not mandatory as part of the procedure for bringing it into compliance with Union requirements)
(clause 1.8.2.5 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
1.8.2.6. A summary of the registration application for generic, hybrid, or biosimilar medicinal products (if applicable). Submission of information is not mandatory for the purposes of the harmonisation procedure with Union requirements.
(Clause 1.8.2.6 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
1.8.2.7. A summary of the registration application if patents exist in a Member State for the medicinal product being registered.
(As amended by Decision of the Council of the Eurasian Economic Commission dated 05.03.2021 No. 14)
1.8.2.8. A summary of the registration application in exceptional cases (if applicable) (submission of information is not mandatory for the purposes of the harmonisation procedure with Union requirements).
(Clause 1.8.2.8 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
1.8.2.9. Summary of an application for registration with the establishment of post-registration measures or Summary of an application for conditional registration (if applicable) (submission of information is not mandatory as part of the procedure for bringing the application into compliance with Union requirements)
(clause 1.8.2.9 as amended by Decision of the Council of the Eurasian Economic Commission of 20.10.2023 No. 114)
1.8.3. Table with a list of clinical trials (if applicable) (submission of information is not mandatory as part of the procedure for bringing the application into compliance with Union requirements)
(clause 1.8.3 as amended by Decision of the Council of the Eurasian Economic Commission of 20.10.2023 No. 114)
1.8.4. Repealed effective 20 December 2023. - Decision of the Council of the Eurasian Economic Commission of 20.10.2023 No. 114
1.9. Applicant's documents on the assessment of potential environmental hazards (if any):
1.9.1. A letter from the applicant stating that the medicinal products contain or are derived from genetically modified organisms (if applicable)
1.10. Information regarding the applicant's pharmacovigilance in a member state of the Eurasian Economic Union
1.10.1. A master file of the pharmacovigilance system of the marketing authorization holder in accordance with the good pharmacovigilance practice of the Eurasian Economic Union or a brief description of the pharmacovigilance system of the marketing authorization holder
1.10.2. Written confirmation that the marketing authorization holder has a qualified person responsible for pharmacovigilance in the territory of a member state of the Eurasian Economic Union.
1.10.3. A risk management plan for the medicinal product submitted for registration in accordance with the requirements of the Good Pharmacovigilance Practice Rules of the Eurasian Economic Union, approved by the Eurasian Economic Commission (if applicable).
1.10.4. Duly certified documents confirming the existence of interactions that ensure the proper performance of all duties of the marketing authorization holder by several legal entities (if applicable).
MODULE 2. SUMMARY OF THE COMMON TECHNICAL DOCUMENT
2.1.
2.1. Contents of Modules 2-5
2.2. Introduction to the CTD
2.3. General Quality Summary
2.4. Overview of Preclinical Data
2.5. Overview of Clinical Data
2.6. Summary of Preclinical Studies
(as amended by Decision of the Council of the Eurasian Economic Commission of 30.01.2020 No. 9)
2.6.1. Introduction
2.6.2. Summary of Pharmacological Studies in Text Format
2.6.3. Summary of Pharmacological Studies in Tabular Form
2.6.4. Summary of pharmacokinetic studies in text format
2.6.5. Summary of pharmacokinetic studies in tabular form
2.6.6. Summary of toxicology studies in text format
2.6.7. Summary of toxicology studies in tabular form
2.7. Summary of clinical studies
2.7.1. Summary of Biopharmaceutical Studies and Associated Analytical Methods
2.7.2. Summary of Clinical Pharmacology Studies
2.7.3. Summary of Clinical Efficacy
2.7.4. Summary of Clinical Safety
2.7.5. Copies of References
MODULE 3. QUALITY
3.1.
3.1. Contents of Module 3
3.2. Basic Information
3.2.S. Active Pharmaceutical Substance (APS). For medicinal products containing several active substances, information is provided in full for each of them. <**>
3.2.S.1. General Information on Starting Materials and Raw Materials <**>
3.2.S.1.1. Information on the API Name <**>
3.2.S.1.2. API Structure <**>
3.2.S.1.3. General Properties of the API <**>
3.2.S.2. API Manufacturing Process
3.2.S.2.1. Manufacturer <**>
3.2.S.2.2. Description of the Manufacturing Process and Its Control
3.2.S.2.3. Control of Starting Materials (submission of information is not mandatory as part of the procedure for bringing the drug into compliance with Union requirements (with the exception of biological medicinal products)). As part of the procedure for bringing a product into compliance with Union requirements, the specified information shall be submitted at the request of the authorized body (expert organization) of a member state of the Eurasian Economic Union during the expert work.
3.2.S.2.4. Control of critical stages and intermediate products (as part of the procedure for bringing a product into compliance with Union requirements, submission of information is optional (with the exception of biological medicinal products)). As part of the procedure for bringing a product into compliance with Union requirements, the specified information shall be submitted at the request of the authorized body (expert organization) of a member state of the Eurasian Economic Union during the expert work.
3.2.S.2.5. Validation and/or assessment of the manufacturing process (as part of the procedure for bringing a product into compliance with Union requirements, submission of information is optional (with the exception of biological medicinal products)). As part of the procedure for bringing a medicinal product into compliance with Union requirements, the specified information shall be provided at the request of the authorized body (expert organization) of a Eurasian Economic Union member state during the expert examination.
3.2.S.2.6. Development of the production process (as part of the procedure for bringing a medicinal product into compliance with Union requirements, the submission of information is not mandatory (with the exception of biological medicinal products)). As part of the procedure for bringing a medicinal product into compliance with Union requirements, the specified information shall be provided at the request of the authorized body (expert organization) of a Eurasian Economic Union member state during the expert examination.
3.2.S.3. Description of the characteristics of the API <**>
3.2.S.3.1. Confirmation of the structure and other characteristics
3.2.S.3.2. Impurities <**>
3.2.S.4. API Quality Control <**>
3.2.S.4.1. Specification <**>
3.2.S.4.2. Analytical Methods <**>
3.2.S.4.3. Validation of Analytical Methods (submission of information is not mandatory as part of the procedure for bringing the product into compliance with Union requirements (with the exception of biological medicinal products))
(clause 3.2.S.4.3 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
3.2.S.4.4. Batch Analysis (Batch Analysis Results) <**>
3.2.S.4.5. Specification Justification
3.2.S.5. Reference Standards or Materials
3.2.S.6. Packaging (Closure) System <**>
3.2.S.7. Stability <**>
3.2.S.7.1. Stability Test Summary and Stability Conclusion <**>
3.2.S.7.2. Post-marketing stability study program and stability commitments (submission of information is not mandatory under the procedure for bringing the drug into compliance with Union requirements (except for biological medicinal products)) <**>
(clause 3.2.S.7.2 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
3.2.S.7.3. Stability test data <**>
3.2.P. Medicinal product
3.2.P.1. Description and composition of the medicinal product
3.2.P.2. Pharmaceutical development
3.2.P.2.1. Components of the medicinal product
3.2.P.2.1.1. Active pharmaceutical substance
3.2.P.2.1.2. Excipients
3.2.P.2.2. Medicinal product
3.2.P.2.2.1. Development of dosage form
3.2.P.2.2.2. Production Surplus
3.2.P.2.2.3. Physicochemical and Biological Properties (submission of information is not mandatory as part of the procedure for bringing the product into compliance with Union requirements (with the exception of biological medicinal products))
(clause 3.2.P.2.2.3 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
3.2.P.2.3. Development of the Manufacturing Process. Submission may be omitted if the medicinal product, manufactured at the same production sites, is registered in all Eurasian Economic Union member states specified in the application for bringing it into compliance with Union requirements (with the exception of biological medicinal products)
(clause 3.2.P.2.3 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
3.2.P.2.4. Packaging (closure) system. Submission is not required if all Eurasian Economic Union member states specified in the application for alignment with Union requirements use the same packaging (closure) system (with the exception of biological medicinal products).
(Section 3.2.P.2.4 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
3.2.P.2.5. Microbiological characteristics (submission of information is not mandatory as part of the procedure for alignment with Union requirements (with the exception of biological medicinal products))
(Section 3.2.P.2.5 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
3.2.P.2.6. Compatibility (submission of information is not mandatory within the framework of the procedure for bringing the Union into compliance with requirements (with the exception of biological medicinal products))
(clause 3.2.P.2.6 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
3.2.P.3. Medicinal Product Manufacturing Process
3.2.P.3.1. Manufacturers
3.2.P.3.2. Batch Composition (Manufacturing Recipe)
3.2.P.3.3. Description of the Manufacturing Process and Its Control
3.2.P.3.4. Control of Critical Stages and Intermediate Products
3.2.P.3.5. Validation and/or Assessment of the Manufacturing Process
3.2.P.4. Quality Control of Excipients
3.2.P.4.1. Specifications
3.2.P.4.2. Analytical Methods
3.2.P.4.3. Validation of analytical methods (within the procedure for bringing into compliance with Union requirements, the submission of information is not mandatory (with the exception of biological medicinal products))
3.2.P.4.4. Justification of Specifications
3.2.P.4.5. Excipients of Human and Animal Origin
3.2.P.4.6. New Excipients (submission of information is not mandatory under the procedure for bringing them into compliance with the Union requirements (with the exception of biological medicinal products))
3.2.P.5. Quality Control of the Medicinal Product
3.2.P.5.1. Specifications
3.2.P.5.2. Analytical Methods
(clause 3.2.P.5.2 as amended by Decision of the Council of the Eurasian Economic Commission of 30.01.2020 No. 9)
3.2.P.5.3. Validation of Analytical Methods
3.2.P.5.4. Batch Analysis Results
3.2.P.5.5. Impurity Characterization
3.2.P.5.6. Specification Justifications
3.2.P.6. Reference Standards and Materials
3.2.P.7. Packaging (Closure) System
3.2.P.8. Drug Product Stability
3.2.P.8.1. Stability Test Summary and Stability Conclusion <**>
3.2.P.8.2. Post-Market Stability Testing Program and Stability Commitments
3.2.P.8.3. Stability Test Data
3.2.A. Appendices
3.2.A.1. Manufacturing Facilities and Equipment
3.2.A.2. Safety assessment of medicinal products for the presence of extraneous agents (submission of information is not mandatory as part of the procedure for bringing them into compliance with Union requirements (with the exception of biological medicinal products))
(clause 3.2.A.2 as amended by Decision of the Council of the Eurasian Economic Commission of 20.10.2023 No. 114)
3.2.A.3. New excipients
3.2.A.3.1. Information on excipients (reducing agents, solvents, diluents, carriers)
3.2.A.3.2. Description and composition of the excipient (reducing agent, solvent, diluent, carrier)
3.2.A.3.3. Pharmaceutical development of the excipient (reducing agent, solvent, diluent, carrier) (submission of information is not mandatory as part of the procedure for bringing it into compliance with Union requirements (with the exception of biological medicinal products))
(as amended by Decisions of the Council of the Eurasian Economic Commission dated 30.01.2020 No. 9 and dated 20.10.2023 No. 114)
3.2.A.3.4. Manufacturing process of the excipient (reducing agent, solvent, diluent, carrier)
3.2.A.3.5. Batch composition (manufacturing formula) of the reducing agent, solvent, diluent, and carrier
3.2.A.3.6. Quality control of the excipient (reducing agent, solvent, diluent, and carrier)
3.2.A.3.7. Microbiological characteristics of the reducing agent, solvent, diluent, and carrier (submission of information is not mandatory as part of the procedure for bringing products into compliance with Union requirements (with the exception of biological medicinal products))
(as amended by Decisions of the Council of the Eurasian Economic Commission of 30.01.2020 No. 9 and of 20.10.2023 No. 114)
3.2.A.3.8. Packaging (closure) system for an excipient (reducing agent, solvent, diluent, carrier)
3.2.A.3.9. Stability of the excipient (reducing agent, solvent, diluent, carrier)
3.2.A.3.10. Information on the compatibility of the reducing agent, solvent, diluent, carrier
3.2.R. Regional information
3.2.R.1. Excluded. - Decision of the Council of the Eurasian Economic Commission dated March 17, 2022 No. 36
3.2.R.2. Manufacturing Process Validation Plan
(clause 3.2.R.2 as amended by Decision of the Council of the Eurasian Economic Commission dated March 17, 2022 No. 36)
3.2.R.3 - 3.2.R.5. Excluded. - Decision of the Council of the Eurasian Economic Commission dated March 17, 2022 No. 36
3.3. Copies of References
MODULE 4. REPORTS ON PRE-CLINICAL (NON-CLINICAL) STUDIES
4.1. Content of Module 4
4.2. Study Reports (if applicable)
4.2.1. Pharmacology
4.2.1.1. Primary Pharmacodynamics
4.2.1.2. Secondary Pharmacodynamics
4.2.1.3. Safety Pharmacology
4.2.1.4. Pharmacodynamic Drug Interactions
4.2.2. Pharmacokinetics
4.2.2.1. Analytical Methods and Validation Reports
4.2.2.2. Absorption
4.2.2.3. Distribution
4.2.2.4. Metabolism
4.2.2.5. Excretion
4.2.2.6. Pharmacokinetic Drug Interactions
4.2.2.7. Other Pharmacokinetic Studies
4.2.3. Toxicology
4.2.3.1. Single-dose toxicity
4.2.3.2. Repeated-dose toxicity
4.2.3.3. Genotoxicity
4.2.3.4. Carcinogenicity
4.2.3.5. Reproductive and ontogenetic toxicity: fertility and early embryonic development, embryofetal development, prenatal and postnatal development; studies on immature offspring with subsequent observation
4.2.3.6. Local tolerance
4.2.3.7. Other toxicological studies: antigenicity, immunotoxicity, studies of the mechanism of action, drug dependence, metabolites, impurities, etc.
4.3. Copies of references
MODULE 5. CLINICAL TRIALS REPORTS
5.1. Contents of Module 5
5.2. List of all clinical studies (trials) in tabular form
5.3. Clinical study (trial) reports
5.3.1. Biopharmaceutical study reports
5.3.2. Pharmacokinetic study reports using human biomaterials
5.3.3. Human pharmacokinetic study reports
5.3.4. Human pharmacodynamic study reports
5.3.5. Efficacy and safety study reports
5.3.6. Post-marketing experience reports
5.3.7. Case report forms and patient lists
5.4. Copies of references
<*> Documents are submitted unless the legislation of a member state of the Eurasian Economic Union prohibits the request from the applicant for documents that are in the possession of or can be obtained independently by the authorized body.
<**> The minimum amount of information required for submission is in Section 3.2.S. If certain types of documents are not included in the dossier, a justification must be provided in the relevant section. For products of animal origin, the following additional information must be provided in Section 3.2.S: information on the species, age, and diet of the animals from which the raw materials were obtained; information on the nature (category) of the tissue from which the raw materials for the production of the medicinal product were obtained, in terms of its prion hazard; a process flow diagram for raw material processing indicating extractants and process parameters; and raw material quality control methods, including methods for detecting prions in the medicinal product (if necessary).
<***> Footnote excluded. - Decision of the Council of the Eurasian Economic Commission dated January 30, 2020, No. 9.
Note:
Unless otherwise provided by the Rules for Registration and Expertise of Medicinal Products for Medical Use approved by the Eurasian Economic Commission, documents certified by the applicant must be submitted. Registration dossier documents must be submitted in Russian or with a Russian translation in accordance with the instructions provided in Part II of this document. It is permissible to submit the document of section 1.6.3 of module 1, as well as the documents of modules 3-5 in English with the mandatory translation into Russian of the following sections of module 3: description of the production process and its control (3.2.S.2.2), control of critical stages and intermediate products (3.2.S.2.4), validation of the production process and (or) its assessment (3.2.S.2.5), impurities (3.2.S.3.2), confirmation of structure and other characteristics (3.2.S.3.1), specification (3.2.S.4.1), analytical methods (3.2.S.4.2), validation of analytical methods (3.2.S.4.3), justification of the specification (3.2.S.4.5), packaging (closure) system (3.2.S.6), summary of stability tests and conclusion on stability (3.2.S.7.1), description and composition of the medicinal product (3.2.P.1), active pharmaceutical substance (3.2.P.2.1.1), excipients (3.2.P.2.1.2), development of dosage form (3.2.P.2.2.1), production surplus (3.2.P.2.2.2), physicochemical and biological properties (3.2.P.2.2.3), development of manufacturing process (3.2.P.2.3), packaging (closure) system (3.2.P.2.4), microbiological characteristics (3.2.P.2.5), compatibility (3.2.P.2.6), description of manufacturing process and its control (3.2.P.3.3), control of critical stages and intermediate products (3.2.P.3.4), validation of manufacturing process and (or) its assessment (3.2.P.3.5), validation of analytical methods (3.2.P.4.3), justification specifications (3.2.P.4.4), excipients of human and animal origin (3.2.P.4.5), new excipients (3.2.P.4.6), specifications (3.2.P.5.1), analytical procedures (3.2.P.5.2), validation of analytical procedures (3.2.P.5.3), characterization of impurities (3.2.P.5.5), justification of specifications (3.2.P.5.6), packaging (closure) system (3.2.P.7), summary of stability studies and stability conclusion (3.2.P.8.1), post-marketing stability program and commitment to stability studies (3.2.P.8.2), safety assessment for adventitious agents (3.2.A.2), new excipients (3.2.A.3), process validation plan (3.2.R.2). Submission of a pharmacovigilance master file in English is permitted, with a mandatory Russian translation of a summary of the marketing authorization holder's pharmacovigilance system and a risk management plan in English, with a mandatory Russian translation of the summary. However, a Russian translation of documents submitted in accordance with paragraph 175.1 of these Rules is not required if Russian is not the official language of the relevant Eurasian Economic Union member state.
(as amended by decisions of the Council of the Eurasian Economic Commission of 23.04.2021 No. 34 and of 17.03.2022 No. 36)
II. Sample list of documents submitted in the registration dossier
modules for different types of medicinal products
Excluded. - Decision of the Council of the Eurasian Economic Commission dated May 22, 2023 No. 60.
Appendix No. 5
STRUCTURE OF THE COMMON TECHNICAL DOCUMENT FOR THE REGISTRATION OF MEDICINAL PRODUCTS
dated January 30, 2020, No. 9, and March 17, 2022, No. 36)
I. Purpose
This document represents a common format agreed upon by the member states of the Eurasian Economic Union (hereinafter referred to as the Member States or the Union) for the submission of a properly structured common technical document (hereinafter referred to as CTD) for registration dossiers submitted to the authorized bodies of the member states.
The common technical documentation format significantly reduces the time and resources spent on compiling registration dossiers for medicinal products for human use and facilitates the electronic submission of documents in the common technical document format (hereinafter referred to as eCTD).
By standardizing common documentation elements, regulatory review and interaction with the applicant are simplified. Furthermore, the exchange of regulatory information between the authorized bodies of the member states is facilitated.
II. Scope of application
This document primarily addresses the organization of information to be submitted in registration dossiers for new medicinal products (including biotechnological medicinal products).
This document does not specify which study results must be submitted. It merely indicates the appropriate format for presenting the obtained data. Applicants are not authorized to modify the fundamental organization of the CTD described in this document. However, in preclinical and clinical summaries, applicants are authorized to modify individual formats if this is required for optimal presentation of technical information to facilitate understanding and evaluation of the results.
III. General principles
To assist the examiner in examining the key data and to help them quickly navigate the contents of the registration dossier, the presentation of information throughout the CTD must be unambiguous and transparent. The margins of text and tables must allow the document to be printed on A4 paper. The left margin must be large enough to prevent damage to the information when stitched (e.g., left margin - 3 cm, right margin - 1.5 cm, top and bottom margins - 2 cm). The font style and size of the text and tables must be large enough to ensure legibility, even after photocopying. It is recommended to use Times New Roman, 12 pt. for narrative text. Each page must be numbered in accordance with the explanatory document (see the appendix to this document). Abbreviations and acronyms should be expanded upon their first mention in each module. References should be given in accordance with the current version of the Uniform Requirements for Manuscripts Submitted to Biomedical Journals of the International Committee of Medical Journal Editors (hereinafter referred to as the ICMED) (The first version of the Uniform Requirements for Manuscripts Submitted to Biomedical Journals was approved by the Vancouver Group and published in 1979).
IV. Organization of a common technical document
The CTD consists of 5 modules. Module 1 is Member State-specific. Modules 2-5 are common to all regions. Compliance with this document must ensure that these 4 modules are presented in a format acceptable to Member State competent authorities.
Module 1. Administrative and Prescribing Information.
This module should contain Member State-specific documents, such as application forms or proposed information on use in Member States. The content and format of this module are described in Appendix No. 1 to the Rules for Registration and Examination of Medicinal Products for Human Use (hereinafter referred to as the Rules).
Module 2. CTD Summary.
Module 2 should begin with a general introduction to the medicinal product, including the pharmacological class, mechanism of action, and intended clinical use. The introduction as a whole should not exceed one page.
Module 2 should contain the following 7 sections in the following order:
CTD Contents;
CTD Introduction;
Quality Summary;
Preclinical Review;
Clinical overview;
Preclinical narrative and tabular summaries;
Clinical overview.
A description of these summaries is provided in Appendix No. 1 to the Rules.
Module 3. Quality.
Quality information must be presented in a structured format in accordance with Appendix No. 1 to the Rules.
Module 4. Preclinical Study Reports.
Preclinical study reports must be submitted in the manner described in Appendix No. 1 to the Rules.
Module 5. Clinical Study Reports.
Human study reports and related information must be submitted in the manner described in Appendix No. 1 to the Rules.
The general organization of the CTD (eCTD) is presented below.
V. SCHEMATIC REPRESENTATION OF THE ORGANIZATION OF THE OTD
Drawing (not shown)
VI. Organization of the Customs Department for the Registration of Medicinal Products for Medical Use
Module 1. Administrative Information
1.2. General Documentation
Module 2. General Technical Document Summary
2.4. Preclinical Data Summary
2.5. Clinical Data Summary
2.6. Preclinical Study Summary
Pharmacology Study Summary
Pharmacokinetic Study Summary
Toxicology Study Summary
2.7. Clinical Study Summary
Biopharmaceutical Study Summary and Associated Analytical Methods
Clinical Pharmacology Study Summary
Clinical Efficacy Summary
Clinical Safety Summary
Copies of References
Individual Study Summary
Module 3. Quality
Module 4. Preclinical (Non-Clinical) Study Reports
4.1. Module 4 Contents
4.2. Study Reports
4.3. Copies of References
Module 5. Clinical Study Reports
5.1. Module 5 Contents
5.2. List of All Clinical Studies (Trials) in Tabular Form
5.3. Clinical Study Reports (Trials)
5.4. Copies of References
VII. Clarification on the location of registration dossier documents
1. Document Definition
When submitting documents on paper, a document is defined as a set of pages, sequentially numbered and separated from other documents by a separator (see the section "Numbering and Separation of Documents" in Appendix No. 4 to the Rules). A document may be considered equivalent to a file when submitted electronically. The level of detail when submitting documents on paper and/or electronically must be the same. However, when updating a paper dossier to an electronic one, certain changes in detail may be required due to ongoing lifecycle management. When submitting documents electronically, the new file must begin at the same location where the documents were separated by separators in the paper dossier.
When determining the relevance of one or more documents or files, it is necessary to keep in mind that the chosen approach must be adhered to throughout the entire lifecycle of the dossier, since any changes to the information require the entire documents (files) to be replaced. The tables below describe the DTD and/or eDTD hierarchy levels at which documents (files) should be located, as well as the need for one or more documents in each location. All DTD and/or eDTD sections are described; however, not all sections may be applicable to individual files.
2. Module 2
Module 2\\\\\\\
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Introduction
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Submission of documents at this level is not permitted..\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\
The content is required only for the paper version of the OTD; it is not provided for in the eOTD.
At this level, one document may be submitted. #
<1> The optional detailing of the quality summary is provided to accommodate the varying complexity of drugs. The applicant has the right to choose the level of preparation of the quality summary.
<2> A separate document must be submitted for each pharmaceutical substance.
<3> If the medicinal product is supplied with solvents for reconstitution, information on the solvents must be provided in a separate section of the "P" document.
<4> A separate document must be submitted for each indication for use; however, similar indications may be presented in a single document.
3. Module 3
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One file per source <6>\\\\
(as amended by decisions of the Council of the Eurasian Economic Commission of January 30, 2020, No. 9,
March 17, 2022, No. 36)
Submission of documents at this level is not permitted. #
The content is required only for the paper version of the OTD; it is not provided for in the eOTD..
At this level, one document may be submitted.\\\\\\\\\\\\\\\\
<1> When selecting the level of detail in this module, the applicant should consider that changes to relevant information at any point during the product's life cycle require replacement of the entire CTD and eCTD documents (files).
<2> If the medicinal product contains multiple active substances, the information required for Section "S" should be provided in full for each active substance.
<3> If the medicinal product is supplied with solvent(s) for reconstitution, information on the solvent(s) should be provided in a separate Section "P," as appropriate.
<4> It is unlikely that the lower level headings included in the quality section of the CTD at this location will be presented as separate documents or files.
<6> The list of references should be included in the table of contents.
4. Module 4
Module 4 #
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<1> For each report included in Module 4, a single document is generally required. However, if the study report is large (e.g., a carcinogenicity study), the applicant may submit the report as multiple documents. In this case, the narrative portion of the report should be presented as a single document, and the appendices should be presented as one or more documents. When choosing the level of detail for these reports, the applicant should consider that changes to relevant information at any point during the life cycle of the medicinal product require replacement of the entire documents (files).
<2> The list of references should be included in the table of contents.
5. Module 5
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5.2 &
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At this level, it is permissible to submit one or more documents..\\\\\\\\\\\\\\\\
<1> Applicants should generally submit study reports in the form of several documents (a synopsis, the main body of the study report, and any necessary appendices). Appendices must be organized in accordance with Appendix No. 1 of the Rules of Good Clinical Practice of the Eurasian Economic Union, which describes the content and format of clinical study reports. When choosing the level of detail for these reports, applicants should take into account that changes to relevant information at any point during the drug's life cycle require replacement of the entire documents (files).
<2> If the registration dossier includes multiple indications for use, this section is duplicated for each indication.
<3> A list of references must be included in the table of contents.
VIII. Numbering and dividing a document
1. General requirements
Each document should be numbered (starting from the first page) with the exception of individual references, for which the actual page numbering in the journal is sufficient. Applicants are not required to provide page numbers as "1 of n," where n is the total number of pages.
In addition, all document pages must include a unique header or footer briefly outlining the document's contents. When submitting paper documents, the document divider should include the same identifier that precedes the document to facilitate its identification in the dossier. Abbreviations of the full section number and document title are permitted.
If a section contains multiple documents, a separate table of contents may be provided for each section (to indicate the chronology and titles of the documents it contains), for example:
divider with "3.2.S.4.2. Analytical Methods";
contents: name of Method A, Method B, Method C;
Separator with "3.2.S.4.2. "Methodology A";
Methodology A (i.e., document, pages 1-n);
Separator with "3.2.S.4.2. "Methodology B";
Methodology B (i.e., document, pages 1-n);
Separator with "3.2.S.4.2. "Methodology C";
Methodology C (i.e., document, pages 1-n).
If a section contains only one document (e.g., "3.2.S.1.1. Nomenclature"), the document should be preceded only by the separator "3.2.S.1.1. Nomenclature".
2. Numbering sections in a document
To avoid subheadings at levels 5, 6, etc. (e.g., 2.6.6.3.2.1), the applicant may use an abbreviated number within the document. In this case, the document number and title (e.g., 2.6.6. Narrative Summary of Toxicology) must be included in the document header or footer, followed by the section number within the document (e.g., 1, 1.1, 2, 3, 3.1, 3.2, etc.). The full number (e.g., 2.6.6.3.2.1) is also acceptable.
3. Formatting content
3.1. Module 2.
The content of section 2.1 of the CTD should be detailed to level 3 (e.g. 2.3.S) or level 4 (e.g. 2.3.S.1) depending on which document is included in the quality summary (see document definition in Module 2).
3.2. Module 3.
The table of contents for Section 3.1 of the CTD should include the top-level section numbers, their corresponding section headings, and the volume number in the order they appear in the file. This table of contents will be used to indicate the contents of Module 3 in accordance with Appendix No. 1 to the Rules. It should be detailed only to level 5 (e.g., 3.2.P.2.1). It should be noted that Appendix No. 1 to these Rules provides for additional subsections and subheadings below this level (e.g., 3.2.P.2), so this format should be used throughout the file, even if not included in Section 3.1. "Contents." The lower-level table of contents described in the "Numbering and Separation of Documents" section should not be included in Section 3.1. "Contents."
At the applicant's discretion, a table of contents may be compiled for a specific section containing multiple documents to provide chronology and numbering beyond those specified in Appendix No. 1 to the Rules. It should be provided only within the document, not as a separate document or a new subheading. In this case, a separate table of contents may be provided for such a document to indicate the chronology and titles of the subsections it contains. These documents and subsections should not be included in Section 3.1. "Table of Contents."
Additional attachments or appendices should not be included in this format; however, they are acceptable as a separate document in a section that allows for the submission of multiple documents. In this case, a reference should be made to the relevant section of the attached or enclosed document. If additional information is desired to be attached or supplemented to a section consisting of only one document, such information should be included in that document.
All table of contents entry names must correspond to the heading names and section numbers in accordance with Appendix No. 1 to the Rules or to the separator identifiers (only when submitting a dossier on paper), preferably by their full name, which should allow for easy identification of any abbreviated names that may be used in the corresponding separator. Page numbers should not be included in the table of contents.
References in the table of contents should refer only to that section.
3.3. Module 4
To identify all important components of the dossier (e.g., 4.2.3.5.1. "Fertility and Early Embryonic Development"), the table of contents for Module 4 must include all numerical elements listed in Appendix No. 1 to the Rules and must be detailed at least to the study report level. Therefore, each study report must be reflected in the table of contents. Sections of the study report may be listed in the table of contents for Module 4 of the dossier or only in the table of contents of a separate study report.
Illustration of part of the table of contents for Module 4.
4.2.3.2. Repeated-Dose Toxicity.
Study aa-aaa: 30-Day Repeated-Dose Toxicity Study of Drug C in Rats.
Study bb-bbb: 6-Month Repeated-Dose Toxicity Study of Drug C in Rats.
Study cc-ccc: 30-Day Repeated-Dose Toxicity Study of Drug C in Dogs. Study dd-ddd: 6-month repeated dose toxicity study of Preparation C in dogs.
4.2.3.3.1. In vitro.
Study ee-eee: Ames test with Preparation C.
etc.
3.4. Module 5.
To identify important components of the dossier (e.g., 5.3.5.1.1. "Placebo-Controlled Studies"), the content of Module 5 must include all numerical elements listed in Appendix No. 1 to the Rules and must be detailed at least to the clinical trial report level. Therefore, each clinical trial report must be reflected in the content. Sections of the clinical trial report (see Appendix No. 1 to the Rules of Good Clinical Practice of the Eurasian Economic Union) may be included in the content of Module 5 of the dossier or only in the content of an individual clinical trial report.
Illustration of part of the content of Module 5.
5.3.5 Indication Z - reports of efficacy and safety studies.
5.3.5.1 Indication Z - reports of controlled clinical trials related to the stated indication for use.
5.3.5.1.1 Indication Z - placebo-controlled trials.
Study xx-xxx: Double-blind, placebo-controlled study of drug A for indication Z.
Study yy-yyy: Double-blind.
5.3.5.1.2 Indication Z - studies with active control.
Study zz-zzz: Double-blind, active-controlled study of drug A versus drug C for indication Z.
5.3.5 Indication Q - Efficacy and safety study reports.
5.3.5.1 Indication Q - Reports of controlled clinical trials relevant to the stated indication.
Appendix No. 6
dated January 30, 2020, No. 9, and May 22, 2023, No. 60)
EXPERT REPORT FORM
ON ASSESSMENT OF THE RESULTS OF PRE-CLINICAL
(NON-CLINICAL) STUDIES
(template)
EXPERT REPORT
on the assessment of the results of preclinical (non-clinical) studies
______________________________________________________
(name of the drug, its dosage, formulation)
Expert:
Procedure commenced:
Date of this report:
Deadline for comments:
ADMINISTRATIVE INFORMATION
Registration Application Identification Number:
Trade Name of the Medicinal Product:
International Nonproprietary Name (INN) or Common Name of the Active Substance(s):
Applicant:
Claimed Indications for Use:
Pharmacotherapeutic Group (ATX Code):
Dosage Form and Strength(s):
Names of the Rapporteur's Experts (Internal Expert and Independent Expert):
Quality:
Full Name:
Phone (Fax):
Email:
Preclinical:
Clinical:
List of abbreviations.
EXAMINATION OF PRE-CLINICAL (NON-CLINICAL) ASPECTS
1. Introduction.
1.1. Application Type and Development Considerations.
1.2. Good Laboratory Practice Considerations.
2. Pharmacology (Modules 2.6.2 and 4.2.1).
Brief Description.
Comments of the expert
Physical and chemical properties.
Active substance structure
(insert structure)
Radiolabel position
(see structure)
Isomerism
Relative molecular weight
Solubility in water
Ionization constant (pKa)
Partition coefficient
Solubility in organic solvents
Stability
Presumed chirality and its effects
2.1. Primary Pharmacodynamics.
Expert Commentary
2.2. Secondary Pharmacodynamics.
2.3. Pharmacological Safety.
2.4. Pharmacodynamic Drug Interactions.
2.5. Overall Expert Pharmacological Conclusion.
3. Pharmacokinetics (Modules 2.6.4 and 4.2.2).
Pharmacokinetic Studies.
3.1. Research Methods.
3.2. Absorption.
Sample tables for entering absorption data:
Study Identification Number
Types
Dosage (mg/kg)
Way of administration
Method of analysis
Cmax
tmax
AUC
A
B
, el
Vd
Clt
F (%)
Notes а)
б)
3.3. Distribution.
3.4. Metabolism.
3.5. Elimination.
Виды
Dose (mg/kg)
Route
Analysis method
Urine (% dose)
Feces (% dose)
Bile (% доза)
Uchanged drug (% dose)
Time (hour)
3.6. Pharmacokinetic Drug Interactions.
3.7. Other Pharmacokinetic Studies.
3.8. Overall Expert Opinion on Pharmacokinetics.
4. Toxicology (Modules 2.6.6 and 4.3.3).
4.1. Single-Dose Toxicity.
Example of a toxicity study table for a single dose:
Study ID
Species/Sex/Number/Group
Dose/Route
Estimated Lethal Dose (Observed Maximum Non-Lethal Dose)
Main Results
Expert comments
4.2. Repeated-Dose Toxicity
Example table for repeated-dose toxicity studies:
Duration
NOEL/NOAEL (mg/kg/day)
Main results
Toxicokinetics.
Example table with data from toxicokinetic studies:
Daily dose (xx/xx)
AUC in animals (ng x h/ml)<*>
Animals: Human
XXX
Re-exposure
Note: <*> For comparison, it is advisable to use AUC values for the unbound fraction of the drug.
Interspecies comparison.
Example table comparing exposure in animal studies with exposure in clinical studies:
4.3. Genotoxicity.
Example of a genotoxicity study overview table:
Assay Type/ID/GLP Compliance
Assay System
Concentrations/Concentration Range/Metabolism System
Results Positive/Negative/Inconclusive
Gene mutations in bacteria
strains of salmonella
+/- S9
Gene mutations in mammalian
cells: Chinese hamster ovary cells (CHO cells), HGPRT locus, human lymphocytes
In vivo mouse chromosomal aberrations
bone marrow micronucleus assay
4.4. Carcinogenicity.
4.4.1. Long-term studies.
Example table describing the studies conducted
on carcinogenic activity:
Identification number/good laboratory practice compliance
Dose/route of administration
Exposure (AUC)
Species/Number of animals
Example table with tumor development data
during Study XX:
Tumor Data
Control
Low Dose
Medium Dose
High Dose
4.4.2. Short- and Medium-Term Studies.
4.4.3. Other Studies.
4.5. Reproductive and Developmental Toxicity.
Example table with data on studies conducted:
Species; number of females/group
Route of administration and dose
Period of administration and dose
NOAEL (mg/kg) и AUC
Male Fertility
Female Fertility
Embryofetal Development F0
F1
Perinatal and Postnatal
4.5.1. Fertility and Early Embryonic Development
4.5.2. Embryofetal Development
4.5.3. Prenatal and Postnatal Development, Including Maternal Function
4.5.4. Studies in Which the Product is Administered to Juveniles and/or Further Evaluated for Development
Conclusions Regarding Reproductive Toxicity
4.6. Local Tolerability
4.7. Other Toxicity Studies
4.7.1. Antigenicity
4.7.2. Immunotoxicity.
4.7.3. Dependence.
4.7.4. Metabolites.
4.7.5. Impurity Studies.
4.7.6. Other Studies.
4.8. Overall Toxicology Conclusion of the Assessing Expert.
5. References.
6. List of Comments Raised by the Expert as Part of the Conducted Evaluation.
CRITICAL COMMENTS
Pharmacology.
Pharmacokinetics.
Toxicology.
MINOR COMMENTS
RECOMMENDATIONS
7. Conditions recommended by the expert, the fulfillment of which is necessary after the applicant receives the registration certificate and approval of the general characteristics of the medicinal product, instructions for medical use (package leaflet), and the packaging design of the medicinal product.
Appendix No. 7
CLINICAL TRIAL ASSESSMENT REPORT FORM
on the evaluation of clinical trials
Administrative information
Trade name of the medicinal product:
International nonproprietary name (INN) or generic name of the active ingredient(s):
Claimed indications for use:
Pharmacotherapeutic group (ATC code):
Dosage form(s) and dosage(s):
Expert contact details:
Expert details (internal and independent):
Expert data (internal and independent):
Clinical Evaluation
1.1. Application type and development aspects:
Type of regulatory registration procedure;
Possibility of applying special grounds for the registration procedure;
Application of the biosimilar concept;
Compliance with drug development guidelines (availability of scientific advice);
Significance of pediatric studies.
1.2. Compliance with Good Clinical Practice (GCP) principles.
1.3. Data on classification as an orphan drug.
According to the conclusion of authorized healthcare authorities (conclusion dated 00/00/00), the incidence rate of the disease (indicate the name of the disease) is (XX) per 10,000 people in the territories of the member states of the Eurasian Economic Union (no data).
2. Clinical pharmacology
2.1. Pharmacokinetics.
2.1.1. Introduction.
2.1.2. Methods.
Analytical Methods and Techniques
Pharmacokinetic Data Analysis
Statistical Analysis
2.1.3. Absorption.
Bioavailability
Bioequivalence
Food Effects
2.1.4. Distribution.
2.1.5. Elimination
Elimination
Metabolism
Interconversion
Pharmacokinetics of Metabolites
Consequences of Possible Genetic Polymorphisms
2.1.6. Dose Proportionality and Time Dependence
Dose Proportionality
Time Dependence
2.1.7. Intra- and Inter-Individual Variability
2.1.8. Pharmacokinetics in the Target Population
2.1.9. Special Populations
Renal Impairment
Liver dysfunction
Expert commentary
Gender
Race
Weight
Elderly
Age 65 - 74 years (number of elderly patients (total))
Age 75 - 84 years (number of elderly patients (total))
Age 85+ years (number of elderly patients (total))
PK research
Children
General Expert Commentary on Pharmacokinetics in Special Populations
2.1.10. Interactions
In vitro
In vivo
General Expert Commentary on Interactions
2.1.11. Exposures Relevant to the Safety Assessment
2.1.12. Overall Expert Opinion on Pharmacokinetics
2.2. Pharmacodynamics
2.2.1. Introduction
2.2.2. Mechanism of Action
2.2.3. Primary Pharmacology
2.2.4. Secondary Pharmacology
2.2.5. Plasma Concentration-Effect Relationship
2.2.6. Pharmacodynamic Interactions with Other Medicinal Products or Substances.
2.2.7. Genetic Differences in Pharmacodynamic Response.
2.2.8. Overall Expert Opinion on Pharmacodynamics.
3. Clinical efficacy
3.1. Introduction.
Sample table for presenting information on study details
Study identification number
Study center numbers (locations)
Design
Study dosage
Study objective
Patients by group (included (completed the study))
Gender (m or f), median age
Diagnosis, inclusion criteria
Primary endpoints
3.2. Dose-Response Studies and Pivotal Clinical Trials
3.3. Dose-Response Study(s)
3.4. Main Study(s)
Methods
Study Participants
Treatment Types
Objectives
Outcomes (Endpoints)
Sample Size
Randomization
Blinding
Statistical Methods
Results
Participant Allocation Flow Chart (this format should be used; modifications may be made as necessary)
(───────────────────────) (───────────────────────)
│ Скринировано │ │Исключены как │
НАБОР │ на соответствие ├────>│несоответствующие │
│ требованиям │ │критериям (n=....) │
│ (n=....) │ │Отказались от участия │
(───────────┬───────────) │(n=....) │
│ │Другие причины (n=....)│
│ (───────────────────────)
\/
(───────────────────────)
│Рандомизировано │
│(n=....) │
(───────────┬───────────)
│
┌──────────────┴──────────────────┐
│ │
\/ \/
РАС- (────────────────────────────────) (──────────────────────────────)
ПРЕ- │Вошли в группу лечения (n=....) │ │Вошли в группу лечения │
ДЕЛЕ- │Получили лечение по протоколу │ │(n=....) │
НИЕ │(n=....) │ │Получили лечение по протоколу │
│Не получали лечения (n=....) │ │(n=....) │
│(указать причину) │ │Не получали лечения (n=....) │
(─────────┬──────────────────────) │(указать причину) │
│ (───────┬──────────────────────)
ПОСЛЕ- (──────────────────────────────) (──────────────────────────────)
ДУЮЩЕЕ │Не вошли в период последующего│ │Не вошли в период последующего│
НАБЛЮ- │наблюдения (n=....) │ │наблюдения (n=....) [указать │
ДЕНИЕ │[указать причины] │ │причины] │
│Лечение прекращено (n=....) │ │Лечение прекращено (n=....) │
│(указать причины) │ │(указать причины) │
(─────────┬────────────────────) (───────┬──────────────────────)
(─────────────────────────) (─────────────────────────)
│Проанализировано (n=....)│ │Проанализировано (n=....)│
АНАЛИЗ │Исключены из анализа │ │Исключены из анализа │
│(n=....) │ │(n=....) │
Study Recruitment
Study Conduct
Initial Data
Analyzed Sample
Outcomes and Their Assessment
Additional Analysis
Summary of Key Efficacy Findings
The following tables summarize the results of the key efficacy studies supporting the adequacy of this statement. This summary should be read in conjunction with the clinical efficacy notes and the risk-benefit analysis (see the following sections).
Summary of Key Study Findings
(Efficacy Study)
Name (as stated in the research report)
Code
List of all codes beginning with the protocol number, followed (if available) by the European Clinical Trials Database number, International Standard Randomized Clinical Trial Number, and other codes for cross-referencing publications.
Study Design
Free text
Describe the key elements of the study design (crossover, parallel, factorial, dose-escalation, fixed-dose analysis), including studies with randomization, blinding, allocation concealment, single- and multi-center studies, etc.
Duration of the main phase:
time
time not applicable
Duration of the preparatory phase:
Duration of the additional treatment phase:
Hypothesis
Advantages
Similarity
No less effective
Overview: Specify
Treatment Groups (add as many rows as needed to describe the treatment groups)
Group coded designation (indicate the abbreviation for later use in the results section table)
Treatment
Number of randomized subjects
Group coded designation
Clinical endpoints (add as many rows as necessary to describe the clinical endpoints;
as secondary clinical endpoints, include the most relevant endpoints listed in the results section)
Combined
Symbol (indicate the abbreviation for later use in the table in the results section)
free text (provide a brief description)
Primary
Clinical Trial Endpoint
Secondary
Other:
Specify the clinical trial endpoint
Symbol
Closing the database
Analyses and results (present separately for each analysis the result considered relevant for inclusion in the study report; in any case, data on the pre-specified primary analysis must be presented)
Description of the Analysis
первичный анализ
Subject Group and Description of Time Points
Sample population
initiated treatment
patients who completed the study according to the protocol
other: specify
(may require a brief description of the population)
time point
Descriptive statistics and estimated variability
Treatment group
coded group designation (according to the terminology given above)
Number of subjects
n
Clinical trial point (symbol as above)
point estimate
Statistic (e.g., mean, median, etc.)
variability
Variance statistics (e.g., standard deviation, confidence interval, etc.)
Clinical trial point (statistic)
Variance statistics Clinical trial point
Statistic
Variance statistics
Estimate of Effect in Comparison (add as many lines as necessary to describe the actual statistical analysis performed)
combined
primary
endpoint of a clinical
trial
Comparison groups
coded group designation (as per the terminology above)
Significance test (e.g., difference between groups)
Variance statistics (e.g., confidence interval, etc.)
variance
P value (specify the statistical method used, e.g., ANOVA)
P value
Indicate the clinical trial location
coded group designation
significance test
variance statistics
укажите точку клинического исследования, пользуясь терминологией, указанной выше в разделе "Точки клинического исследования и определения"
P-value
Notes
(Among other things, consider the following information:
Reasons for withdrawal from the study; Critical analysis results)
Analysis Description
Additional analysis
Combined primary analysis
Other
Specify (also indicate if the analysis was planned)
Repeat the above sections for each relevant analysis
3.5. Clinical trials in special populations.
Controlled studies
Uncontrolled studies
3.6. Analysis performed within the context of trials (pooled analysis and meta-analysis).
3.7. Additional research.
3.8. Overall Expert Opinion on Clinical Efficacy
Clinical Efficacy Conclusions
Clinical Trial Design and Conduct
Efficacy Data and Additional Analyses
4. Clinical safety
4.1. Introduction.
4.2. Drug Exposure to Patients.
Sample Table: Drug Exposure to Patients (Acceptable Levels)
Included patients
Patients who received treatment
Patients exposed to the proposed dose range
Patients with long-term <*> safety data
Placebo-controlled studies
Active-controlled studies
Open-label studies
Post-marketing studies
Compassionate use
<*> The indication applies to data from continuous or intermittent exposure over a period of 6 or 12 months.
4.3. Adverse events.
4.4. Serious adverse events and death.
4.5. Laboratory test data.
4.6. Safety of drug use in special population groups.
Dictionary terms MedDRA
age < 65 years, number (percentage)
age 65 - 74 years, number (percentage)
age 75 - 84 years, number (percentage)
ge 85+ years, number (percentage)
Total number of adverse events
Serious adverse events (total)
Fatal
Hospitalization (prolongation of existing hospitalization)
Life-threatening
Disability (incapacity)
Other (medically important)
Adverse event leading to study withdrawal
Psychiatric disorders
Nervous system disorders
Accidents and injuries
Cardiac disorders
Vascular disorders
Cerebral circulatory disorders
Infectious and parasitic diseases
Anticholinergic syndrome
Decreased quality of life
In summary: orthostatic hypotension, falls, blurred vision, syncope, dizziness, ataxia, fractures
Other adverse events more common in elderly patients
4.7. Immunological phenomena.
4.8. Safety in drug and other interactions.
4.9. Withdrawal from the study due to adverse events.
4.10. Post-market studies.
4.11. Overall conclusion of the clinical safety assessor.
Clinical efficacy conclusions
Clinical safety conclusions
5. Pharmacovigilance
5.1. Pharmacovigilance system.
The applicant submitted documents detailing the pharmacovigilance system. The pharmacovigilance application is signed by the applicant and the authorized representative, stating that the applicant is provided with the services of an authorized representative responsible for pharmacovigilance and has the necessary means to report any adverse reaction occurring in the Eurasian Economic Union or a third country.
The expert considers that the pharmacovigilance system described by the applicant satisfies the requirements and provides adequate evidence that the applicant is provided with the services of an authorized representative responsible for pharmacovigilance and has the necessary means to report any suspected adverse reaction occurring in the Eurasian Economic Union or a third country.
The expert considers that the pharmacovigilance system described by the applicant has the following deficiencies: <list of deficiencies>.
Given that deficiencies are corrected before the applicant launches the medicinal product, the authorized expert organization can deem the pharmacovigilance system compliant. Before a medicinal product is marketed, the applicant must provide convincing evidence that the pharmacovigilance system is in place and functioning.
5.2. Risk Management Plan.
Questions and/or comments for consideration by the pharmacovigilance expert when assessing the risk management plan: _______________________________________________________________________
______________________________________________________________________
6. Bibliography:
_______________________________________________________________________
7. List of questions raised by the expert
Clinical aspects:
a) Critical comments:
pharmacokinetics;
pharmacodynamics;
efficacy;
safety;
pharmacovigilance system;
risk management plan;
b) Minor comments:
c) Recommendations:
8. Conditions recommended by the expert, compliance with which is required after the applicant receives a registration certificate and approval of the general characteristics of the medicinal product
Applicant consultation:
Your name
Your phone
Your email (required)
Choose the topic of your message
Your message