Requirements for a drug registration dossier in the Eurasian Economic Union (EAEU)

APPENDIX № 1 to the Rules for registration and examination of drugs in the Eurasian Economic Union (EAEU)

REQUIREMENTS
to the documents of the drug registration dossier
(in the format of the Common Technical Document (CTD)

 

Part I. General requirements for the modules of the drug registration dossier, accompanying the application for registration of the drug within the framework of the Eurasian Economic Union (EAEU)

1. Requirements to the documents of the registration dossier given in Module 1: Administrative information.

1.0. Cover letter (as in the general technical document (hereinafter - CTD)).

In this section, you must include a cover letter to the application.
If necessary, as an attachment to the cover letter, it is allowed to submit the document "To the Experts' Notice", providing more detailed information in order to improve the navigation (for example, on hyperlinks, the location of volumes, etc.).

1.1. Content.

It is necessary to present the complete content of Modules 1-5 of the registration dossier.

1.2. General Documentation:

1.2.1. The application for registration of the medicinal product (on paper and electronic carriers in the formats * .doc / *. Docx and * .pdf) is filled in the form according to Appendix 2 to these Rules.

1.2.2. Documents confirming the payment for expert works and (or) payment of the registration fee (fee) in accordance with the national legislation of the Member State of the EAEU carrying out the registration of the medicinal product.

1.2.3. Certified copy of the Certificate of Pharmaceutical Product certified according to the format recommended by WHO, issued by the competent authority of the country of manufacture (if available).

In the absence of such a certificate, a document confirming the drug registration in the producing country and / or in the country-holder of the registration certificate for the pharmaceutical product (certified in accordance with the established procedure) (if any).
In the absence of drug registration in the producing country or country-holder of the registration certificate, an explanatory note is provided explaining the lack of data on drug registration.

1.2.4 Translation into Russian and a certified copy of the expert report of the authorized body regarding drug registration in the country of the manufacturer or in the country of the holder of the registration certificate (if any).

1.2.5. Conclusion (recommendation) of the authorized body (authorized organization) of the EAEU member state based on the results

1.2.6. Recommendation of the Expert Committee on Medicines for the Eurasian Economic Commission (hereinafter - the Commission) on the results of prior scientific advice on this medication (if any).

1.3. Summary of Product’s Characteristics (hereinafter - SmPC), instructions for medical use (leaflet-insert) (hereinafter - IFU), marking:

1.3.1. Projects of SmPC, IFU, compiled in accordance with the requirements of the EAEU in Russian.

1.3.2. Mock-ups of primary, secondary and intermediate packages, compiled in accordance with the requirements of the EAEU in Russian. Mock-ups of intermediate packaging, labels, stickers are provided when available.

1.3.3. Results of user testing of IFU text (if applicable).

• When presenting the results of user testing, it is necessary to summarize briefly how the testing was conducted and how all the necessary changes were made to the final version of the IFU. The summary should be presented in this section of the module, in the following form:
• a brief description of the medicinal product;
• a brief description of the testing conducted or the study of individual elements of the IFU (the methodology used, explanations on the criteria for selecting participants for testing, the language of testing);
• used questionnaires (questionnaires, including instructions on how to fill them in and forms of observation);
• initial and revised version of the IFU;
• a brief description and discussion of the test results (subject replies, identified problems and changes made to the relevant sections of the IFU); conclusion.
• All other details must be submitted upon request to the authorized body (expert organization).

1.3.4. Copies of SmPC and IFU, approved by the authorized body of the country of origin and / or country of the drug registration certificate with the date of the last revision, certified by the authorized person of the holder of the registration certificate (if any).

1.4. Information on the regulatory status of the drug in other countries (if available).

1.4.1. The list of countries in which the drug is already registered, or still under registration, was denied registration or suspended from registartion, indicating the name of the medicinal product, number and the date of the drug registration certificate, its validity, or the date of making decisions to refuse registration, suspension of the validity of the registration certificate; the information provided must be certified by the holder of the registration certificate of the drug.

1.5. Documents on quality:

1.5.1. Certificate of compliance with the article of the EAEU Pharmacopoeia or the European Pharmacopoeia on spongiform encephalopathy or a document issued by the authorized veterinary supervision authorities of the country of origin of raw materials in case of use of pharmaceutical substances of animal origin (if available).

1.5.2. Letter from the holder of the master file of the Active Pharmaceutical Ingredient accepting the obligation to report all changes to the manufacturer of the finished dosage from and the authorized body of the Member State of the EAEU before any significant changes are made to the master file of the pharmaceutical substance (an original letter with the signature of the authorized person for quality with translation ).

1.5.3. A letter confirming the consent of the holder of the master file of the API to submit documents of the closed part of the master file to the API at the request of the authorized body.

1.5.4.    A copy of the certificate of compliance of the pharmaceutical substance with the requirements of the European Pharmacopoeia (if available).

1.5.5. Copy of the certificate to the master plasma file issued by the authorized body (if available).

1.5.6. Copy of the certificate for the master file of the vaccine antigen issued by the authorized body (if available).

1.6. Documents on production:

1.6.1. A certified copy of the current document (certificate) confirming the conformity of the manufacturer (production site) of the medicinal product claimed for state registration with the requirements of the GMP of the EAEU issued by the authorized body of the state member of the EAEU.
Certified copies of valid certificates confirming GMP manufacturer's compliance issued by the authorized authorities of the country (countries) in which the production site (production sites for different production stages) is located and (or) by other authorized body. If available provide an address of the Internet site of the register issued by the authorized body of GMP conformity certificates (for example, EudraGMP) (if applicable).

1.6.2. Certified copies of the acting manufacturing permit (license) (with attachments) issued by the authorized body of the country in which manufacturing  site is located (production sites for different stages of production).

1.6.3. Certified copy of the report (s) inspection of the manufacturing site (production sites for different production stages) for compliance with GMP standards  conducted by the authorized body of the producing country or by the other authorized body for the last 3 years with a plan and report on corrective actions (CAPA) after the inspection (if any) and a link to the site of the authorized body on the basis of GMP inspections (for example, EudraGMP) (if available).

1.6.4. A certified copy of the contract (agreement) between the holder of the registration certificate and the manufacturer in compliance with GMP requirements if the holder of the registration certificate does not participate in the production of the drug.

1.6.5. A certified copy of the contract (agreement) between the contract manufacturing site and the manufacturer in compliance with the requirements of GMP, if the whole process or one of the stages of the drug production is performed on the contract production site.

1.6.6. Information on any regulatory measures taken by the authorized body during the last 3 years based on the results of inspections with respect to the declared production site (if any).

1.6.7. Letter of the authorized person on the quality of the conformity of the conditions for the production of the drug claimed for registration with the requirements of the proper production practice of the EAEU, including the same for the raw materials for each production site used in the production of the medicinal product and active pharmaceutical substance, including the sites under inspection quality and control in the production process. The letter must be signed by an authorized person for quality and certified with a stamp (stamp) of the manufacturer, if necessary with translation into Russian.

1.6.8. Information about complaints regarding the quality of medicinal products produced at the production site of the medicinal product claimed for registration for the last three years, or confirmation of the absence of complaints.

1.6.9. Consent to conduct a pharmaceutical inspection for compliance with the requirements of the EAEU.

1.6.10. A copy certified by a producer of the main dossier of the production site (master file) (if applicable).

1.6.11. The scheme of production stages with the indication of all production sites involved in the production process of the medicinal product and active pharmaceutical ingredient, including the batch release testing.
 

1.7 Information about specialists:

1.7.1. Information about a specialist who prepared a resume on quality.

1.7.2. Information about a specialist who prepared a resume on preclinical data.

1.7.3. Information about a specialist who prepared a resume on clinical data.

Information on quality specialists, preclinical and clinical data includes information on their education, specialization and professional experience, should be signed by specialists who compiled a resume and a survey of quality, preclinical, clinical data. These specialists must have appropriate qualifications. It should be indicated the existence of a professional relationship between the specialist who compiled the resume and the applicant.

1.8. Specific requirements for different types of applications:

1.8.1. A letter from the holder of the drug registration certificate of the additional trade name of the medicinal product should be provided if the applicant plans to register the medicinal product under different trade names in the country of the producer, in the referring state and in the state of recognition. The letter should indicate the assurance that one registration dossier is used for this purpose. The letter must be signed by the holder of the drug registration certificate and dated.

1.8.2. Clinical research documents (if applicable):

1.8.2.1. Permission of the authorized body to conduct a clinical trial, including all of the amendments.

1.8.2.2. The list of GCP inspections carried out for the drug submitted for registration with the indication of authorized bodies conducting inspections, dates, results (if any).

The list of inspections includes:

• Inspection of research centers involved in clinical trials of the drug;
• inspection of the sponsor or contract research organization for clinical trials of the medicinal product or
• inspections of other organizations relevant to the study, for example, the analytical laboratory involved in clinical trials of the drug;
• other GCP-inspection.

If the clinical study is carried out completely in the research centers of third countries, the results of the GCP inspection (s) carried out in the research centers in which the maximum number of patients were included in the study of this drug should be included in the list. Inspections can be conducted for another study, including another drug, the owner of the registration certificate for which is not the applicant. In this case, the authorized bodies (expert organizations) independently request reports of such inspections from the relevant regulatory authorities) and they are not provided in section 18.3.3. module 1 of the registration dossier.

1.8.2.3. Copies of the reports on the conduct of the items listed in paragraph 1.8.3.2. of this annex to the GCP inspection rules for clinical trials of medicinal products (if any).

1.8.2.4. Copy (s) of the contract (s) between the clinical research sponsor and the research center (contract research organization), if necessary after the seizure of confidential information.

1.8.3. Table with a list of clinical trials (if applicable).

1.8.4. A letter of the holder of the registration certificate of the drug on the conformity of clinical trials of the drug submitted for registration with the requirements of the proper clinical practice of the EAEU.

1.9. The applicant's documents on the assessment of potential environmental hazards (posted as Appendix No. 1 to the module) (if any).

1.9.1. Letter from the applicant that the medicinal products contain genetically modified organisms or were derived from them (if applicable).

1.10. Information on the pharmacovigilance of the applicant in the Member State of the EAEU.

1.10.1. The master file of the pharmacovigilance system of the holder of the drug registration certificate in accordance with the good practice of the EAEU pharmacovigilance is provided in case the holder of the registration certificate of the drug applies at the first time for drug registration in the unified market of the EAEU.

For subsequent applications for drug registration, a brief description of the pharmacovigilance system of the holder of the drug registration certificate is provided on behalf of this holder of the registration certificate.

A brief description of the pharmacovigilance system of the holder of the drug registration certificate should include, inter alia, the following elements:

• written confirmation that the holder of the drug registration certificate has at his disposal an authorized person responsible for pharmacovigilance. If the holder of the registration certificate of the drug is not located in the territory of the EAEU member states, confirmation of the presence of a contact person for pharmacovigilance in the territory of a member state of the EAEU is also required;
• the indication of the state in which the authorized person resides and performs his functions;
• contact details of the authorized person and contact person (if applicable);
• a declaration / declaration signed by the holder of the drug registration certificate stating that he undertakes to fulfill the tasks and responsibilities listed in the Good Pharmacovigilance Practice of the EAEU;
• link to the location (address) of the master file of the pharmacovigilance system.

1.10.2. Written confirmation from the holder of the drug registration certificate that he has at his disposal a qualified person responsible for pharmacovigilance in the territory of a member state of the EAEU.

1.10.3. The risk management plan for the medicinal product, which is submitted for drug registration in accordance with the good pharmacovigilance practice of the EAEU. The risk management plan can be submitted electronically, with the mandatory provision of a resume on paper (if applicable).

1.10.4. Documents duly certified confirming the existence of interaction ensuring the proper performance by several legal entities of all the obligations of the holder of the registration certificate in the event that the holders of registration certificates of the medicinal product issued by the reference state and the recognition states are different legal entities.

1.11. Copies of documents confirming the registration of the trademark (if any).

2. Requirements to the documents of the registration dossier given in Module 2: Summary of the General Technical Document (DTD).

The module provides a summary of the chemical and biological documentation, preclinical and clinical data presented in Modules 3, 4 and 5 of the registration dossier of a drug, as well as a summary of independent experts.

Generalized factual data are presented, including materials in the form of tables. These reports provide cross-references to tables or information contained in the main documentation presented in Module 3 "Quality", Module 4 "Pre-clinical (non-clinical) reports" and Module 5 "Clinical Trials Reports".

Reviews and summaries must comply with the basic principles and requirements set out below.

2.1. Contents of Modules 2, 3, 4, 5.

In this module section, the contents of the scientific documentation presented in Modules 2-5 are presented.

2.2. Introduction to CTD.

Information on the pharmacological group, the mechanism of action and the proposed clinical use of the drug should be provided.

2.3. General summary of the quality.

A general summary of the quality should provide an overview of information related to chemical, pharmaceutical and biological data.
It is necessary to pay special attention to the main critical parameters and issues related to quality aspects, as well as to provide a justification in cases when the relevant requirements and installations are not met. This document should cover issues and describe relevant data, which are covered in details in Module 3.

2.4. Overview of preclinical data.

It is necessary to provide a generalized and critical assessment of preclinical studies of the drug on animals in vitro, as well as discussion and justification of the research strategy, if it is necessary to deviate from the relevant requirements.

For all drugs with the exception for drugs of biological origin, it is necessary to include an assessment of impurities and decay products of the medicinal product together with their potential pharmacological and toxicological effects. Any differences in the chirality, chemical form and purity of compounds used in preclinical studies and in the drug to be produced should be considered.

For medicinal products of herbal or biological origin, it is necessary to evaluate the comparability of the material used in preclinical studies, clinical trials in the drug claimed for registration.
Any new excipient is subject to a separate safety assessment.

It is necessary to determine the properties of the drug, proven in preclinical studies, and to present the significance of the safety results of the drug for the planned clinical use with human participation.

2.5. Review of clinical data.

The review of clinical data should contain a critical analysis of the clinical data that is included in the summary and Module 5. It is necessary to provide information on the method of clinical drug development, including the design of the trial, the decisions taken in relation to the trial, and the progress of the clinical trials.

It is necessary to provide a brief overview of the clinical trial data, including important limiting factors, as well as an assessment of the benefit / risk ratio that is based on the findings of clinical trials, to justify the proposed dose and indications for use based on the clinical efficacy and safety data, and to evaluate how to optimize the benefit and limit the risks by using the general characteristics of the drug, instructions for medical use and other approaches.

It is necessary to explain all the questions regarding the efficacy and safety that arised during the development process and which have not been explained.

2.6. Summary of preclinical research.

The summary of preclinical data should be presented on the basis of the actual results of pharmacological, pharmacokinetic and toxicological studies conducted in animals in vitro, in text format and in tabular form in the sequence shown below, with an introductory part.

2.6.1. Summary of pharmacological data in text format.

2.6.2. Summary of pharmacological data in the form of tables.

2.6.3. Summary of pharmacokinetic data in text format.

2.6.4. Summary of pharmacokinetic data in the form of tables.

2.6.5. Summary of toxicological data in text format.

2.6.6. Summary of toxicological data in the form of tables.

2.7. Summary of clinical data.

It is necessary to provide a detailed summary of the clinical summary of clinical information on the drug included in Module 5. The summary should include the results of all biopharmaceutical research, clinical pharmacology research, and clinical efficacy and safety trials. It is necessary to provide a brief overview of individual studies. Clinical information in the form of a summary should be presented in a certain sequence by part (with a list of used literature sources).

2.7.1. Summary of biopharmaceutical research and related analytical methods.

2.7.2. Summary of studies on clinical pharmacology.

2.7.3. Summary of clinical efficacy.

2.7.4. Summary of clinical safety.

2.7.5. A copy of the literary sources used.

2.7.6. Brief review of individual studies.

3. Requirements to the documents of the registration dossier given in Module 3: Quality.

 

3.1. Content of Module 3.

3.2. The basic information required for the presentation includes:

a) chemical, pharmaceutical and biological data on active pharmaceutical ingredients and a drug, including information on the development, production process, characteristics and properties, methods and requirements for quality control, stability, and a description of the composition and packaging of the drug;

b) the main parts of the information on the active pharmaceutical substance and the drug;

c) detailed information on the raw materials and raw materials used in the production of active pharmaceutical substances and excipients included in the composition of a medicinal product;

d) all test methods and methods used in the production and quality control of the API and a medicinal product, set out clearly and in detail, so that they can be reproduced during the control tests at the request of the authorized body. All test methods should correspond to the current scientific level and be validated. The results of the validation of the methodologies should be presented. When using the test methods included in the EAEU Pharmacopeia, the pharmacopoeias of the EAEU member states and the main pharmacopoeias, in accordance with the Concept of Harmonization of Pharmacopoeias of the Member States of the EEMP (hereinafter referred to as the "Concept"), reference to the monograph (s) and the general section s) should be provided;

e) for all APIs listed in monographs of the EAEU Pharmacopoeia, pharmacopoeias of the EAEU member states and basic pharmacopoeias, in accordance with the Concept, reference should be made to the listed pharmacopoeias.
However, if the pharmaceutical substance specified in the Pharmacopoeia of the EAEU, the pharmacopoeia of the parties and the main pharmacopoeias, in accordance with the Concept, is prepared in a manner in which impurities not controlled by the monograph of the above pharmacopoeias can arise, then these impurities and their tolerable content should be indicated, and to present a methodology for their determination. If the specification included in the monograph of the Pharmacopoeia of the EAEU, the pharmacopoeia of the parties and the main pharmacopoeias, in accordance with the Concept, is not sufficient to ensure the quality of the substance, a more detailed specification may be required from the manufacturer or the holder of the registration certificate.
If the methods and methods of analysis are included in the EAEU Pharmacopoeia, the need for their full presentation is not available, and it is sufficient to cite the relevant reference to the monograph (s) and general section (s);
f) If raw materials and active pharmaceutical substances or excipients are not described in the above pharmacopoeias, then reference to a monograph of a pharmacopoeia of another country may be acceptable. In such cases, the applicant must submit a copy of the monograph together with the validation of the analytical techniques described in the monograph and, if necessary, translation;

g) if the active pharmaceutical substance and / or excipient and raw material are described in the monograph of the European Pharmacopoeia, the applicant can submit the certificate of conformity with the monograph of the European Pharmacopoeia in the relevant paragraph of this module. It is recognized that the certificates of compliance with the monograph of the European Pharmacopoeia replace the essential data in the relevant sections indicated in this module. The manufacturer of the substance must confirm in writing to the applicant that the production process has not changed since the issuance of this certificate of conformity;

h) for well-known (existing for at least 10 years from the date of the first systematic and documented use of the active substance (s) of the medicinal product in all EAEU member states, with the exception to biological), the manufacturer of an API or the applicant for the drug registration can draw up a separate document, including the following information (dossier or master file of the API):

detailed description of the production process;
quality control in the production process;
report on the validation of the production process.
The manufacturer of an active pharmaceutical substance has the right to send a master file of an active pharmaceutical ingredient to the authorized body of the state member of the EAEU.
When using the master file of an active pharmaceutical substance in the registration dossier of a drug, the manufacturer of such an active pharmaceutical ingredient must provide the applicant (holder of the registration certificate) of the relevant medicinal product with all the necessary data in order to bear the liability provided for in these Regulations. The manufacturer of an active pharmaceutical ingredient must provide the applicant (the holder of the drug registration certificate) with a written confirmation guaranteeing the consistency of the quality of the series, and that no changes will be made to the production process or specifications of such an active pharmaceutical ingredient without notification of the applicant (holder of the registration certificate of a drug). The documents and data necessary for making such a change must be submitted to the authorized body; these documents and data are also submitted to the applicant on sections relating to the open part of the master file of the active pharmaceutical substance.
If the applicant does not have full information regarding the closed part of the master file of the active pharmaceutical ingredient from which it is made, because of its confidentiality, the written permission from the manufacturer of this active pharmaceutical ingredient is attached to the application, provided that information about API is included in the Unified Register. This authorization should grant to  the authorized body the right to use the previously submitted information of the closed part of the master file of the active pharmaceutical ingredient in the examination of the drug.

i) it is necessary to describe special measures to prevent the transmission of animal spongiform encephalopathies (raw materials obtained from ruminant animals): at each stage of the production process, the applicant must confirm the compliance of the materials used with the requirements of the Guidelines for minimizing the risk of transmission of germs of spongiform encephalopathies of animals according to the Pharmacopoeia of the EAEU with medicinal products, or submit a certificate of compliance with a specific monograph of the European Pharmacopoeia, or scientific evidence to justify this compliance effects;

j) Information on the assessment of the risk of potential contamination by extraneous agents (virus or non-viral nature) should be provided in accordance with the requirements set forth in the special manuals, as well as in general articles (monographs) and general sections of the EAEU Pharmacopoeia, pharmacopoeia of parties and main pharmacopoeias, in accordance with Concept;

k) it is necessary to describe in detail the special devices and equipment used at any stage of the production process and the control phase of the medicinal product;

l) If necessary, documents confirming the registration of the medical device should be submitted in accordance with the rules approved by the Commission.

3.3. Active Pharmaceutical Ingredient.

3.3.1. General information on raw materials and substances:

a) information on the name of the API, including the recommended INN, if available, is a pharmacopoeial name, according to the EAEU Pharmacopeia and the chemical name in accordance with the IUPAC nomenclature.
Structural formula is presented, including relative and absolute spatial structure, molecular (empirical) formula and relative molecular mass. For biotechnological drugs, if applicable, it is necessary to provide a schematic sequence of amino acids and a relative molecular weight.
For biological medicinal products it is necessary to provide a list of physico-chemical and other important properties of the active pharmaceutical ingredient, including their biological activity;
b) in the context of this paragraph, the source materials consider all materials from which the active pharmaceutical substances are produced or allocated.
For medicinal products of biological origin, starting materials are any materials of biological origin, such as microorganisms, organs and tissues of plant or animal origin, cells or liquids (including blood or plasma) of humans or animals, biotechnological cellular components (recombinant or non-recombinant cell substrates, including primary cells).
A medicinal preparation of biological origin (in the context of this paragraph) is considered to be all medicinal preparations, the active substance of which is a biological substance (material).
Biological substance is a substance obtained from a biological source, in order to describe and confirm the quality of which it is necessary to present a combination of physical, chemical and biological methods of analysis together with a description of the production process and its control.
Any other substance that is used to manufacture or isolate the active ingredient or active ingredient, but from which this active ingredient or active ingredient is not directly produced, namely: reagents, nutrient media, embryo serum, embryo, supplements, and buffers used in preparative chromatography etc., are considered to be raw materials.

3.3.2. The process of production of an active pharmaceutical ingredient:

a) the applicant must provide a description of the production process of the active pharmaceutical ingredient. For a proper description of the production process and its control, the necessary information must be stated in accordance with the requirements established in the relevant guidelines of the EAEU;

b) all raw materials and materials necessary for the production of an active pharmaceutical ingredient must be listed with an indication of the stage of production on which each type of raw material is used. It is necessary to provide information on their quality and control, as well as information confirming compliance with the requirements (standards) for the intended use. It is necessary to list the raw materials (raw materials), as well as to provide documentation on quality and quality control. It is necessary to provide the name and location of the production sites and indicate the responsibilities of each manufacturer, including contract manufactures, as well as information on each of the used production sites or testing laboratories;

c) the following additional requirements have been established for biological medicinal products.

It is necessary to provide a description and a documentary confirmation of the origin and a history of the source materials.

Regarding special measures to prevent the transmission of pathogens of spongiform encephalopathy, the applicant must confirm that the active substance meets, in particular, the requirements of the relevant article (monograph) of the EAEU Pharmacopoeia to minimize the risk of transmission of pathogens with manufactured medicinal products.

When using cell banks, there is evidence that the characteristics of the cells remained unchanged with the number of passages that are used for production, and also during the next period.

Sown materials, cell banks, serum or plasma pools and other materials of biological origin, and, if possible, the materials from which they are obtained, are examined for the presence of foreign agents.

If the presence of potentially pathogenic extraneous agents can not be avoided, then materials can only be used if, in subsequent processing, the removal and / or inactivation of data from outside agents is ensured, and this should be validated.

Wherever possible, the production of vaccines should be based on a system of inoculum cultures and known cell banks. In the production of bacterial and viral vaccines, the characteristics of the causative agent of infection should be demonstrated on the seed material. In addition, for live vaccines, the stability characteristics of attenuation (weakening virulence of pathogenic microorganisms) should be confirmed on the seed material; if such proof is not enough, the attenuation characteristics should also be confirmed at the production stage.

For medicinal products derived from human blood or plasma, in accordance with the provisions set out in Part 3 of this Annex, it is necessary to describe and document the origin, criteria and methods of selection, transportation and storage of raw materials.

It is necessary to describe the production facilities and equipment;

d) where applicable, information on tests and eligibility criteria at each critical stage, information on the quality and control of intermediate products, and on process validation and / or evaluation;

e) if the presence of potentially pathogenic extraneous agents can not be avoided, then materials may only be used if subsequent processing provides for their removal and / or inactivation, as evidenced by the validation and given in the relevant section on the evaluation of viral safety;

f) it is necessary to provide for an active pharmaceutical ingredient the description and analysis of the significant changes made to the production process during development and / or at the production site, and (if the manufacturer of the medicinal product is not an active pharmaceutical ingredient manufacturer) to provide a copy of written commitment of the manufacturer of  an active pharmaceutical ingredient to inform the applicant about changes in the production process or specifications (in an arbitrary form).

3.3.3. 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 physico-chemical and / or immunochemical, and / or biological methods, and information on impurities should be provided.

3.3.4. Quality control of an active pharmaceutical ingredient:

It is necessary to provide detailed information on the specifications used for the serial control of an active pharmaceutical ingredient, the rationale for the selection of these specifications, test procedures and validation.
It is necessary to present the results of quality control of individual series produced at the development stage.

3.3.5. Standard samples or materials:

It is necessary to define and describe in details standard materials and standard samples. Where possible, appropriate pharmacopeial chemical reference materials and biological standard materials should be used.

3.3.6. Packing / Sealing System:

A description of the primary packaging and the packaging / closure system and the specification of its components should be provided.

3.3.7. Stability:

a) it is necessary to present a summary of the studies conducted, the plans (programs) used and the results obtained during the research;
b) it is necessary to provide the detailed results of the stability study, including detailed information on the analytical methods used and their validation;
c) it is necessary to submit a plan (program) for the study of stability during the post-registration period and the obligations of the applicant for its implementation.

3.4. P. Medicinal preparation.

3.4.1. Description and composition of the medicinal product.

It is necessary to provide a description of the medicinal product and its composition. Information should include a description of the dosage form and composition with a list of all components of the finished medicinal product, their quantity in terms of unit dose, the functional purpose of the components:
active pharmaceutical ingredient;
auxiliary substance (s), regardless of its origin or quantity, including dyes, preservatives, modifiers, stabilizers, thickeners, emulsifiers, flavors and fragrances, etc .;
components of the dosage form, external envelopes of medicinal products that enter the patient's body when taken orally, or by any other route of administration (hard capsules, soft capsules, rectal capsules, film-coated tablets, film-coated tablets, etc.);
this information should be supplemented by any significant data related to the type of container and, if applicable, the method of its closure, together with detailed information on the devices by which the medicinal product will be used or introduced and which will be supplied with the drug.
The term "accepted terminology", which is used to describe the components of drugs, regardless of the application of other provisions, means the following:
for substances having an INN recommended by WHO - INN or, in the case where the substance is in a salt, ester, hydrated or other form, a corresponding modified INN;
for other substances (in the absence of INN) - a common (grouping) name, taking into account salt, ether, hydrate and other forms; in the absence of the generally accepted (grouping) name, the chemical name for the IUPAC nomenclature, and in the absence of the latter, data are given on the sources and methods of preparation, the presence of additives introduced, and others (if necessary with appropriate detailed details).
for dyes - in addition to the name, the corresponding code should be given, according to the International Numbering System for food additives Codex Alimentarius (E-codes).
In the section "the quantitative composition" of the drug for an active pharmaceutical ingredient, it is necessary, depending on dosage form, indicate the mass or number of units of biological activity per dosage unit dosage form, or per unit of mass, or per unit of volume of each active pharmaceutical ingredient.
If the active pharmaceutical ingredients are presented in the form of compounds or derivatives, then it is necessary to present their quantitative expression, indicating their total mass, and, if necessary, the mass of the active part of the molecule.
For drugs containing the active pharmaceutical ingredient, which is declared for the first time in the composition of the drug, the amount of active pharmaceutical ingredient that is a salt or a hydrate must always be indicated in terms of the weight of the active part of the molecule.
With regard to drugs containing an active pharmaceutical ingredient firstly registered in a medicinal product in a Member State of the EAEU, the quantity of such an active pharmaceutical ingredient, if it is a salt or a hydrate, must be expressed according to the system approach by the mass of the active part of the molecule. The quantitative content of the same active pharmaceutical ingredient in all subsequent drugs registered in the Member States of the EAEU must be indicated in the same way.
For a substance or active substance that can not be chemically determined, indicate units of biological activity or, if any, international units of biological activity established by WHO. If WHO international units are not established, units of biological activity should be expressed in such a way as to provide accurate information on the activity of a substance or active substance, using, where appropriate, units of the EAEU. If possible, the biological activity per unit mass should be indicated.

3.4.2. Pharmaceutical development:

This section contains information on development studies conducted to prove that:
- dosage form;
- composition;
- manufacturing process;
- packaging / sealing system;
- microbiological characteristics;
- instructions for preparing the final dosage form suitable for direct use
comply with the intended use specified in the drug registration dossier of the applicant.
The studies described in this section differ from the roIFUne control tests carried out in accordance with specifications. It is necessary to define and describe the critical parameters of the composition and the characteristics of the process, which can affect the reproducibility of the series, the effect and quality of the drug. If necessary, when submitting additional confirmatory data, reference should be made to the relevant items of Module 4 "Pre-clinical (non-clinical) reports" and Module 5 "Reports on clinical trials (trials)" of the drug registration dossier:
a) the compatibility of the active pharmaceutical ingredient with the excipients must be justified, as well as the basic physicochemical properties of the active pharmaceutical ingredient that may affect the characteristics of the drug, or the compatibility of the different active pharmaceutical ingredients with each other in the case of combined medicines;
b) the choice of excipients needs to be justified, especially with regard to their respective functional characteristics and content;
c) it is necessary to provide a description of the development of the medicinal product, taking into account the proposed route of administration and the method of application;
d) the presence of any excess in the drug composition should be justified;
e) it is necessary to specify and justify any physico-chemical and biological properties and any parameters affecting the characteristics of the medicinal product;
f) it is necessary to provide information on the selection and optimization of the production process, as well as on the differences (discrepancies) between the manufacturing process used in the production of the series involved in the phases of clinical trials and the planned industrial process for the production of the finished drug;
g) it is necessary to substantiate the suitability of the primary package and the closure system, which is used for storage, transport and use of the drug. It may be necessary to describe the potential interaction between the drug and the primary packaging material;
h) for both non-sterile and sterile medicinal products, it is necessary to present the microbiological characteristics of the dosage form in accordance with the requirements of the EAEU Pharmacopoeia;
i) the compatibility of the drug with the solvent (s) intended for dilution before use or with a dispenser must be justified in order to provide relevant additional information on the use of the solvent (s) or dispenser (dosing device).

3.4.3. The process of production of the medicinal product:

a) a description of the method of production specified in the application for state registration of the drug is presented in such a way as to provide an adequate summary of the nature of the operations performed.
To this end, it should include, at a minimum: a description of the various stages of production, including control in the production process and appropriate acceptance criteria to assess whether the processes used in production can cause any undesirable changes in the components of the dosage form;
in the case of a continuous production process - a description of the measures necessary to ensure the uniformity of the drug; experimental research on validation; production process using non-standard methods of production or if it is critical for the medicinal product;
for sterile medicinal products - a description of the existing sterilization processes and / or procedures to ensure aseptic conditions;
detailed production recipe (composition per series).
You must provide name and location of production sites and indicate the responsibilities of each manufacturer, including contract manufacturers, as well as information on each of the used production sites or testing laboratories;
b) it is necessary to provide a description of analytical techniques for drug quality control that can be used at intermediate stages of the process to ensure uniformity of the production process.
These techniques are important from the point of view of checking the compliance of the drug with the production formulation, especially when the applicant offers an analytical technique for drug control that does not include the quantification of all active pharmaceutical ingredients (or all excipients that must meet the same requirements as do active pharmaceutical ingredients).
This also applies to cases in which the quality control of a drug depends on intra-production tests, especially when the method of production of the medicinal product significantly affects its quality;
c) it is necessary to provide a description, documentation and results of validation studies for critical production points or methods of quantification used in the production process.

3.4.4. Quality control of excipients:

a) A list of all raw materials used for the production of excipients should be provided, indicating in which stage of the process each one is used. Information should be provided on the quality and quality control of these raw materials, a;omg with information that indicates that the materials meet the standards in terms of their intended use.
In all cases, the dyes must satisfy the requirements of the relevant article (monograph) of the EAEU Pharmacopoeia and the requirements of the Technical Regulations of the Customs EAEU "Safety Requirements for Food Additives, Flavors and Technological Auxiliaries" (TR TS 029/2012), in addition, the dyes must meet the purity criteria established by requirements of the documents of the EAEU.
b) for each excipient, the specifications and their justification shall be provided. It is necessary to describe and properly validate the analytical techniques used to monitor their quality;
c) special attention should be paid to excipients of human or animal origin.
In order to comply with special measures to prevent the transmission of pathogens of spongiform encephalopathy of animals, the applicant must also confirm for excipients that the medicinal product meets, in particular, the requirements of the relevant article (monograph) of the EAEU Pharmacopoeia for minimizing the risk of transmission of pathogens with produced drugs.
Compliance with the above requirements can be confirmed by submitting a certificate of compliance of the monograph of the European Pharmacopoeia with regard to causative agents of spongiform encephalopathy or other documents (data) that justify this compliance;
d) new excipients:
For excipients that are used for the first time in a medicinal product or are used for a new route of administration for these excipients, a complete description of the production, properties and control should be provided, with reference to confirmed preclinical and clinical safety data. This information should be formatted as described above for an active pharmaceutical ingredient.
It is necessary to provide detailed chemical, pharmaceutical and biological information. This information should be formatted as indicated in Module 3 for an active pharmaceutical ingredient.
The information on the new excipient can be presented 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 separate document must be submitted by the manufacturer to the applicant.
Further information on the results of a toxicity study for a new excipient should be provided in Module 4 of the drug registration dossier.
The results of clinical trials for the new excipient should be described in Module 5.

3.4.5. Quality control of medicinal product.

In order to control the quality of a medicinal product under a series of medicinal products, it means products that include the whole number of units of the medicinal product produced from the same amount of raw materials and raw materials and subjected to the same production and / or sterilization operations, or, in the continuous production process, all units of the medicinal product, produced in a certain period of time, characterized by uniformity.
The maximum permissible deviation of the active pharmaceutical ingredient content in the medicinal product at the date of its production shall not exceed ± 5%, except for appropriately justified cases.
It is necessary to provide detailed information about the specifications (during production and during the expiration date / shelf life based on the stability tests carried out) with the justification for their selection, test procedures and validation.

3.4.6. Standard samples and materials:

It is necessary to define and describe in details standard materials and standard samples used in the control of the quality of the medicinal product, unless information on them is indicated in the section on the active pharmaceutical ingredient.

3.4.7. Packaging / Sealing System:

It is necessary to provide a description of the primary packaging and closures, along with their specification including description of the materials from which each component of primary packaging in made. Specifications should include a description and identification of materials. If necessary, information on non-pharmacopoeial methods (including validation of the methods) should be provided.

For non-functional secondary, intermediate packaging materials, only a brief description is provided. For functional components of the secondary and intermediate packaging, additional information is presented.

3.4.8. Stability of the drug:

a) a summary of the types of studies conducted, the plans (programs) used and the results obtained during the research;

b) it is necessary to provide the detailed results of the stability study in the appropriate format, including information on the analytical techniques used and their validation.
For vaccines, if necessary, provide information on cumulative stability;

c) it is necessary to submit a plan (program) for studying stability during the post-registration period and the applicant's obligations for its implementation.

3.5. A. Additions.

3.6. A. 1. Production facilities and equipment.

3.7. A.2. Evaluation of safety with respect to foreign agents.

3.8. A.3. New auxiliary substances.

3.9. R.I. Dossier of the production site.

3.10. R.2. The validation master plan.

3.11. R.3. The latest review on the quality of the drug

3.12. R.4. Quality manual or Laboratory manual.

3.13. R.5. A list of analytical techniques that is performed by the manufacturer's quality control laboratory.

 

4. Requirements to the documents of the registration dossier given in Module 4: "Pre-clinical (non-clinical) reports"

 

4.1. Content of Module 4.

4.2. Reports on research.

In some cases, according to the requirements of Part II of this Annex and the rules of the EAEU for the study of individual drug groups, a literature review can be presented in this section instead of the data of own preclinical studies.

Documents of the registration dossier on pharmacological and toxicological tests should determine:

a)    Potential toxicity of the medicinal product and any harmful or undesirable toxic reactions that may occur under the proposed conditions of human use; their evaluation should be given taking into account the corresponding pathological conditions;

b)    pharmacological properties of the medicinal product according to qualitative and quantitative indices, according to the declared clinical application. All results must be reliable and generally applicable. When planning experimental studies and evaluating received data, it is necessary to use methods of mathematical and statistical processing of the results.

In addition, the registration dossier should provide information for medical professionals on the therapeIFUc and toxicological potential of the drug.

For biological drugs, such as immunological drugs and drugs derived from human blood and plasma, adaptation of the requirements of this module to a specific drug may be required, and therefore the applicant must provide a justification for the trial program used.

In the drug registration dossier of the research program, it is necessary to take into account that:

all trials requiring repeated administration of the drug should be planned taking into account the possible stimulation of antibody formation and the effect of antibodies on the body;
it is also necessary to consider the feasibility of conducting research on reproductive function, embryonic / fetal and perinatal toxicity and possible mutagenic and carcinogenic effects. If the cause of toxicity is not the active substance (hereinafter referred to as the active substance) but other substances, then it is possible not to carry out the studies, provided that the validation results confirm that these components are removed from the medicinal product.
If the excipient is used in pharmaceutical practice for the first time, it is necessary to conduct its toxicological and pharmacokinetic studies.
If there is a possibility of a significant disintegration of the drug during storage, it is necessary to consider conducting a toxicological study of the decay products.

4.2.1. Pharmacology:

The registration dossier on pharmacological research should highlight two different aspects:

firstly, the pharmacodynamic activity of the drug proposed for therapeIFUc use should be appropriately studied and described. Whenever possible, recognized and validated research methods should be used, both in vivo and in vitro methods. The description of new experimental techniques should be sufficiently described to ensure their reproducibility. The results should be presented by quantitative indicators, for example, dose-effect curves and / or time-effects, and the like. The results should be compared with data characterizing a substance or substances with a similar therapeIFUc effect. The absence of comparative studies should be justified;
Secondly, the applicant must examine the potential undesirable pharmacodynamic effects of the substance on physiological functions. Such a study should be carried out at exposures corresponding to the expected therapeIFUc range of doses and exceeding it. If experimental methods are not standard, they should be sufficiently detailed and validated to be able to reproduce them and confirm their validity. Any quantitative changes in reactions that occur in response to repeated administration of the active substance should be investigated.
Documents of the registration dossier on the study of fixed combinations of active substances with respect to their pharmacodynamic interaction should be based either on pharmacological assumptions or on indications for their use. In the first case, a pharmacodynamic study should confirm those interactions that make such a combination meaningful for therapeIFUc use. In the second case, when the scientific justification for such a combination of substances is based on experimental research, the study establishes the possibility of confirming on animals the actions that are expected from such a combination of substances and, at least, the significance of any identified concomitant effects.

4.2.2. Pharmacokinetics.

Documents of the drug registration dossier on pharmacokinetic studies include an analysis of all processes occurring with the active substance and its metabolites in the body and cover the study of absorption, distribIFUon, biotransformation and removal of these substances.

The study of each of these stages can be performed either by physical, chemical or biological methods, or by studying the actual pharmacodynamic activity of the active substance itself.
Information on distribIFUon and excretion from the body is necessary to provide in all cases when such data are mandatory for the determination of doses for humans, as well as for chemotherapeIFUc substances (antibiotics, etc.) and substances whose use depends on their non-pharmacodynamic effects (for example, diagnostic drugs and etc.).

It is advisable to conduct In vitro studies with  use of human test systems instead of use of animal test systems (eg, protein binding, metabolism, drug interactions).

In the drug registration dossier, it is necessary to present the results of pharmacokinetic studies of pharmacologically active substances. When used new fixed combinations of known active substances that have already been examined in accordance with the provisions of this Regulation, information on pharmacokinetic studies may not be available if such a decision is justified by the results of toxicity studies and experimental therapeIFUc studies.

The pharmacokinetic research program should provide a comparison of data for animals and humans and extrapolation to humans of the results obtained in animals.

4.2.3. Toxicology:

4.2.З.1. Toxicity in case of single administration:

Documents of the drug registration dossier for toxicity studies in a single administration include a qualitative and quantitative analysis of toxic manifestations that may occur as a result of a single administration of the active substance or substances contained in the drug in the same proportions and physico-chemical state as in the finished medicinal product.
Toxicity tests for a single administration should be carried out in accordance with the guidelines of the Commission or, if they are not available, appropriate guidelines of the EAEU member states;

4.2.3.2. Toxicity in case of repeated (repeated) administration.

Documents of the registration dossier for toxicity studies with repeated (multiple) administration should be aimed at identifying any physiological and / or pathoanatomical changes resulting from repeated administration of the active substance or a combination of active substances and determining how these changes depend on the dosage.
In the drug registration dossier, it is preferable to provide information from two studies: short-term, 2-4 weeks long and long-term study. The duration of the latter depends on the duration of clinical use of the drug. Its purpose is to experimentally identify and describe potential adverse effects that must be considered in clinical trials;
The duration of toxicity tests for repeated administration should be done in accordance with the guidelines of the Commission or, if they are not available, appropriate to the guidelines of the EAEU member states.

4.2.3.3. Genotoxicity.

The drug registration dossier provides information on mutagenic and clastogenic potential of a drug, with the purpose to identify violations that can be caused by the active substance in the genetic material of an individual organism or in cells. Mutagenic substances are dangerous to human health, since the mutagen causes mutations in the sex cells and the generation of hereditary disorders, as well as in somatic cells, which can lead to the development of malignant tumors. These studies are mandatory for all new active substances;

4.2.3.4. Carcinogenicity.

The registration dossier of the drug provides information on carcinogenic potential studies, which are usually conducted if:
the drug is intended for prolonged continuous or intermittent (intermittent) use throughout the life of the patient;
In carrying out toxicity studies with repeated administration of the drug, some changes were identified that led to suggestions about their carcinogenic potential;
the active substance belongs to the chemical class or closely to the known carcinogens or co-carcinogens (a drug of the same class or similar structure, or based on toxicity data from repeated administration).
It is not necessary to carry out such studies with unconditionally genotoxic compounds, since they are considered to be carcinogens that pose a danger to humans. If such a drug is intended for long-term treatment of patients, a long-term study may be required to detect an early oncogenic effect;

4.2.3.5. Reproductive and ontogenetic toxicity.

The registration dossier of a drug provides information on studies of possible reproductive harm in men and women, as well as negative effects on offspring, which are carried out through appropriate tests. These include studies of the effect on the reproductive function of sexually mature male and female animals, studies of the toxic and teratogenic effects on the offspring at all stages of development from conception to sexual maturity as well as latent effects, when the study drug was administered to pregnant female animals.
The absence of such studies in the drug registration dossier should be appropriately justified.

Depending on the indications for the use of the drug, additional studies (influence on the development of the offspring) may be required when the administration of the drug to immature animals is justified.

Documents of the drug registration dossier on pre-clinical studies should contain information on the study of embryo-fetal toxicity, which are usually carried out on two types of mammals, one of which should not be rodents. Studies of perinatal and postnatal toxicity should be conducted on at least one species of animals. If it is known that the metabolism of the active substance for a certain animal species is similar to that in humans, it is advisable to use this species when carrying out research. It is also desirable that one of the species be the same as that used in conducting toxicity studies with repeated administration;

In determining the design of the study, the level of scientific knowledge at the time of application should be taken into account.

4.2.3.6. Local tolerability

Documents of drugs registration dossier on preclinical studies should provide information on local tolerability, whose purpose is to study and determine the local action of the drug (active substances and excipients) to the body tissue in those areas that can be contacted with a drug, as a result of its administration in clinical use .

The research strategy should be aimed at distinguishing any mechanical effect of the administration or the effect caused by the physico-chemical properties of the drug from the toxic or pharmacodynamic effect.

The drug registration dossier should provide proved infromation that the local tolerance study was performed using a drug developed for human use, during which the carrier / diluent is administered to animals of the control group for the administration of the test drug and / or excipients. If necessary, information should be provided on the additional inclusion of a positive control group or a reference substance.

The design of local tolerability studies (choice of animal species, duration, frequency, mode of administration, dose) depends on the research objectives and the expected features of the clinical use of the drug. If necessary, the applicant should provide information on the conducted studies of the reversibility of local injuries.

Information on animal studies can be replaced by test data using validated techniques in vitro if the results of the studies are of comparable quality and are suitable for safety analysis.
For chemicals used topically (eg, dermal, rectal, vaginal), their sensitizing potential should be assessed using at least one test system (study in guinea pigs or local lymph nodes).

5. Requirements to the documents of the registration dossier given in Module 5: Reports on clinical trials.

 

5.1. Content of Module5.

5.2. The list of all clinical studies (tests) in the form of tables:

Particular attention should be paid to presenting of the following information in the drug registration dossier.

a) clinical information, which should allow to generate sufficiently substantiated and scientifically reliable conclusions as to whether the drug meets the registration conditions. An important requirement is that the results of all clinical trials are favorable, as well as unfavorable / negative;

b) Clinical trials should always be preceded by appropriate pharmacological and toxicological studies conducted on animals, information on which is given in Module 4 of the registration dossier.

The researcher should familiarize himself with the conclusions drawn from the results of pharmacological and toxicological studies, and therefore the applicant must submit to him at least a researcher's brochure, which should include all relevant information known at the commencement of clinical trials, including chemical, pharmacological and biological data, results of toxicological, pharmacokinetic and pharmacodynamic studies in animals, as well as the results of previous clinical trials, represent adequate data to justify the nature, scale and duration of the planned study; full reports of pharmacological and toxicological studies should be submitted on request. When using materials obtained from humans or animals, all measures must be taken before the start of the study to ensure safety from the point of view of the transmission of infectious agents;

c) Holder (holders) of the drug registration certificate must ensure that the main clinical trial documentation (including individual registration cards) is kept by the owners of the results obtained, with the exception of the medical records of inpatients / outpatients (patients):
at least, within fifteen years after the completion or termination of the study or,
at least for two years after the last registration in the member states of the EAEU, provided that there are no pending approval or applications for registration in the EAEU or,
at least for two years after the formal discontinuation of the clinical development of the investigational drug was done.
Medical records of inpatient / outpatient patients (patients) should be stored in appropriate conditions and within the period stipulated by the current legislation of the EAEU member state and in accordance with the maximum period of time allowed by the clinical center, an institute or a private practice institution. Documents can be stored for a longer period of time if required by relevant regulatory rules or by agreement with the sponsor of the study. Notifying the clinical center, the institute or the institution of private practice that there is no more any need to store documents is the responsibility of the research sponsor. The research sponsor or other owner / data owner must store all other research related documentation for the entire period during which the drug has a registration certificate. This documentation includes: a protocol containing the rationale, objectives, statistical plan and methodology of the tirial with the conditions for its conduct, organization / management, detailed information on the study medication used, the standard used / the reference and / or the placebo; standard operating procedures; all written feedback on the protocol and procedures; a researcher's brochure; individual registration card of each subject of the study; final report; certificate of audit, if any. The final report shall be kept by the research sponsor or his legal successor within five years after the expiration of the validity of the registration certificate for the drug. The holder of the drug registration certificate must take additional measures to archive the documentation in accordance with good clinical practice and the introduction of detailed guidelines / recommendations. Information about any change in the ownership of existing data should be properly drawn up; all data and documents must be submitted at the request of the relevant authorized bodies.

d) the description of each clinical trial should contain sufficient information to form an objective conclusion: a clinical trial protocol containing the rationale, objectives, statistical plan and methodology of the study with the conditions of its conduct and organization, and detailed information about the study medication;
certificate of audit (if any);
list of researchers;
each researcher must provide his name, address, position, qualifications and responsibilities for conducting clinical trials;
indicate where the study was conducted, provide information on each individual patient, including individual registration cards
the final report signed by the researcher, and in a multicentre study by all researchers or the coordinator (chief investigator);

e) the above-mentioned data of clinical trials should be submitted to the authorized bodies of the EAEU Member States responsible for registration of drugs. However, the applicant is entitled not to submit part of such information if it is agreed with the authorized bodies. Full documentation should be submitted on request immediately.
The clinical trial report should reflect the opinion of the researcher on the basis of experimental evidence of drug safety under normal conditions of use, its tolerability, efficacy, any useful information regarding indications for use and contraindications, dosing regimens, duration of therapy, and special precaIFUons to be taken during treatment and when clinical symptoms of an overdose appear. In the report on the results of the multicenter study, which is presented in the registration dossier, the research coordinator in his conclusions should express an opinion on the safety and efficacy of the investigational drug on behalf of all the centers during the multicentre study;

f) clinical observations for each type of study should be generalized indicating: the number and gender of subjects receiving drugs; selection and distribIFUon by age of patients in the study and control groups; the number of patients who left the study ahead of schedule and the reasons for this; if the controlled studies were performed under the conditions indicated above, indicate what happened to the participants in the control group (did not receive treatment, received a placebo, received another medication with a known effect, received a different kind of treatment without using drugs); frequency of observed undesirable reactions; information on patients at high risk, for example, elderly people, children, pregnant women or women of reproductive age, or patients whose physiological or pathological condition requires special attention;
parameters or criteria for assessing effectiveness and the results obtained;
statistical evaluation of the results, if required by the design of the study, and various factors affecting it.

g) the drug registration dossier should display information on the observation of the researcher about: any signs of addiction, dependence or difficulties in patients arising from the withdrawal of the drug; any interactions that occur with simultaneous administration with other drugs; criteria that determine the need to exclude some patients from the study; lethal cases during the study or during follow-up.

h) the information on a new combination of active substances should be identical to the data on the new drug and in the registration dossier it is necessary to include a rationale for the safety and effectiveness of the combination.

i) in case of complete or partial absence of the above data in the drug registration dossier, an explanation of the reason must be provided. If unexpected results are obtained during clinical trials, additional preclinical toxicological and pharmacological studies should be performed and an overview of the results obtained.

j) if the drug is intended for long-term use of a patient, a description of any changes in the pharmacological effect as a result of repeated use of the medicinal product must be provided in the registration dossier, and it is also necessary to justify the choice of dosages for long-term use.

5.3. Reports on clinical trials (trials).

5.3.1. Biopharmaceutical research reports.

The registration dossier of a drug should include reports on bioavailability, comparative bioavailability, bioequivalence, in vitro in vivo correlation and description of bioanalytical and analytical techniques. In addition, if it is necessary to demonstrate the bioequivalence of drugs, information should be provided on the evaluation of their comparative bioavailability.

If a biowaiver is used in the drug registration dossier, a report on in vitro research should be submitted. Evaluation and implementation of bioequivalence trials or justification for its non-conduct should be submitted in accordance with the requirements of the Rules for bioequivalence study of medicines of the EAEU.

5.3.2. Reports on pharmacokinetic studies using human biomaterials.

Biomaterials derived from humans include proteins, cells, tissues and associated materials derived from humans that are used in in vitro or in vivo studies to evaluate the pharmacokinetic properties of the active substances. In the drug registration dossier, reports should be submitted on the study of binding to plasma proteins, liver metabolism and interaction of the active substance, as well as studies using other biomaterials obtained from humans.

5.3.3. Reports on pharmacokinetic studies in humans:

a) in the registration dossier, the following pharmacokinetic characteristics should be described: absorption (speed and degree); distribIFUon; metabolism; excretion. Information should be provided on the description of clinically important characteristics, including the importance of kinetic data in determining the dosage regimen for patients at risk, and the differences between humans and animal species used in pre-clinical studies.

In the registration dossier, in addition to information on standard pharmacokinetic studies using a significant number of samples in the analysis of population pharmacokinetics based on sparse sampling during clinical trials, information on the effect of internal and external factors on the variability of the relationship between dose and values of pharmacokinetic parameters / reaction can be provided. Reports on the pharmacokinetics study and the first studies on the tolerability of the drug by healthy volunteers and patients, pharmacokinetics studies reports to assess the impact of internal and external factors, and reports on population pharmacokinetics should be submitted;

b) if the drug is usually used in conjunction with other medicinal products, a description of the study of their simultaneous use, which was conducted to demonstrate a possible change in the pharmacological effect, should be provided in the registration dossier of a drug. It is necessary to provide information on the pharmacokinetic interaction of the active substance with other drugs or substances.

5.3.4. Reports on pharmacodynamic studies in humans:

a) the drug registration dossier has to confirm the correlation of pharmacodynamic effects and efficacy, including: the dose-response relationship and its development over time; substantiation of the dosing regimen and conditions of administration; mechanism of action, if possible. It is necessary to provide a description of the pharmacodynamic effect, not related to efficacy. The confirmation of pharmacodynamic effects in humans should not in itself be sufficient justification for the presence of any specific therapeIFUc effect;
b) if the medicinal product is usually applied together with other medicinal products, a description of the study of their simultaneous use, which was conducted to demonstrate a possible change in the pharmacological effect, should be provided. It is necessary to indicate the information on the study of the pharmacodynamic interaction of the active substance with other drugs or substances.

5.3.5. Reports on the study of efficacy and safety.

5.З.5.1. Reports on controlled clinical trials to confirm the declared indications for use.

Information should be provided on clinical trials that, if possible, should be randomized and controlled, where the study drug is compared with a placebo and / or a drug with proven therapeIFUc effectiveness, the use of any other design of the study should be justified. The choice of control groups differs in each case depending on ethical aspects and scope, therefore, in some cases, it is more appropriate to compare the effectiveness of a new drug with the efficacy of a drug with proven therapeIFUc effectiveness than with placebo.

When presenting the assessment, measures should be applied to avoid bias, including methods of randomization and blind control.

The clinical trial protocol contained in the drug registration dossier should include a description of the statistical methods used, the number of patients and the reasons for including them (including calculations of the statistical power of the studies), the level of significance used and the description of the statistical unit (statistical parameters used). Measures taken to avoid biased assessment, especially methods of randomization, should be appropriately justified and documented. Information on the inclusion of a large number of patients for participation in the study should not be considered an equivalent substitute for an appropriately controlled trial.

When analyzing safety data, attention should be paid to the circumstances that led to the adjustment of the dosing regimen or the need for concomitant use of another drug, serious adverse events, phenomena that led to expulsion from the study and resulted in death. It is necessary to identify patients or groups of patients with high-risk studies and pay special attention to potentially vulnerable groups, the number of which may be small, for example, children, pregnant women, elderly people with weakened health, people with significant metabolic or excretion disorders, etc. A final safety assessment of the possible uses of the drug should be described.

5.3.5.2. Reports on uncontrolled clinical trials, reports on data analysis for several studies and reports on other clinical trials.
These reports must be included in the registration dossier.

5.3.6. Reports on the post-registration experience of application of a drug.

If the medicinal product is already registered in other countries, the registration dossier should provide information on adverse reactions to the drug and medications with the same active substance, if possible, in comparison with the extent of their clinical use.

5.3.7. Individual registration cards and patient lists.

Individual registration cards and patient lists are attached to the registration dossier, which must be submitted in the same manner as clinical research reports with indexation for the study, while maintaining the confidentiality of the personal data of the study patients.

Data of laboratory and instrumental methods of research, statistical processing of the results of clinical studies.

Part II. special requirements to the modules of the registration dossier, accompanying the application for registration of the medicinal product

6. Requirements to the documents of the registration dossier of the reproduced drugs

The registration dossier of the reproduced medicinal product is provided in accordance with the requirements of this section, taking into account the Rules for conducting bioequivalence studies of drugs in the Eurasian Economic Union.

The choice of the reference preparation in bioequivalence studies is carried out in accordance with the Rules for conducting bioequivalence studies of medicinal products in the Eurasian Economic Union.

For a replicated drug, bioequivalence to the original drug should be demonstrated by appropriate bioavailability studies in accordance with the Rules for Conducting Studies on Reproduced Medicines in the Eurasian Economic Union.

SmPC and IFU of the reproduced drug should be consistent with SMPC and IFU of the original drug. In the case of a difference in indications for use in the direction of expansion, or the dosage regimen or route of administration, the results of appropriate clinical trials should be provided in the instructions for the medical use of the reconstituted drug from the original medicinal product.

6.1. Module 1

In section 1.8.2. the applicant must provide brief information (up to 5 pages), which summarizes the reasons and facts used to show that the drug intended for registration is:

reproduced drug of the corresponding original medicinal product; this summary should contain information about the preparation, its qualitative composition and the quantitative content of the active pharmaceutical substance, its dosage form and safety profile, and (or) the effectiveness of its active substance as compared with the active substance of the original preparation, as well as, if necessary, information on bioavailability and bioequivalence of this drug;

in certain cases, a risk management plan may be required.

In the absence of certain elements, a justification for their absence should be provided in the relevant section.

6.2. Module 2

In the review of preclinical and clinical data, particular attention should be paid to the following elements:

• a summary of the profile of impurities of the active substance (and, if applicable, possible decomposition products formed during storage) in the series of the drug that is to be sold on the pharmaceutical EAEU market;
• evaluation of bioequivalence studies or an explanation of why such studies have not been conducted;
• updating of literature publications on the active substance within the framework of this application for drug registration; this requirement can be fulfilled by referring to articles in peer-reviewed journals;
• Each item in the general characteristic of the medicinal product, previously not known or resulting from the characteristics of the drug and / or its therapeutic group, should be analyzed in pre-clinical and clinical reviews (summary) and should be supported by evidence from published literature and / or from additional studies;
• with the difference in the chemical forms of the active substance: salts, esters, isomers, mixtures of isomers, complexes or derivatives of the active substance of the original preparation, additional information should be provided proving that the safety profile and (or) the efficacy of the claimed preparation do not differ from those of the original preparation .

6.3. Module 3

Module 3 should be presented entirety.

6.4. Modules 4 and 5

The results of bioequivalence studies conducted in cases where this is necessary should be included in section 5.3.1. The results of the equivalence proof for the biowaiver procedure should be presented in section 5.3.1.2. It is also necessary to provide a report on the validation of the bioanalytical method. It is also necessary to provide data on concentration, pharmacokinetics and statistical analysis.

The report should include information about the researcher (s) and the organization where they work, the place (organization) and the period of the study. It is necessary to attach audit certificates to the report, if available.

The study report or a separate official letter should confirm the selection of the reference medication in accordance with the Rules for Conducting Bioequivalence Studies of Medicinal Products in the Eurasian Economic Union, as well as the following information about the reference drug - trade name, dosage, dosage form, holder of the drug registration certificate, date of registration, registration certificate number, state (s) - member (s) of the EAEU, where the reference drug is registered, serial number, manufacturer's name, expiration date and country of purchase. If needed -  provide a recommendation of the Expert Committee on Medicines under the Eurasian Economic Commission for the selection of the reference preparation.

It is necessary to indicate the name and composition of the test drug (s), the size of the lot, the date of manufacture, and, if possible, the expiration date.

In the annex to the study report, it is necessary to add the analysis certificates for the series of reference drugs and test drugs used in the study.

It is necessary to provide a document (official letter) signed by an authorized person on the quality of the manufacturer and confirming that the quantitative composition and production of the test drug is identical to the quantitative composition and production of the drug submitted for registration.

If the chemical forms of the active substance are different: salts, esters, isomers, mixture of isomers, complexes or derivatives from the active substance of the reference drug, additional information (in accordance with the structure of the general technical document) should be provided, proving that the safety and (or) effecicacy profiles of the claimed drug do not differ from those of the reference medicinal product.

The results of preclinical studies, clinical trials of the reproduced medicinal product, carried out when necessary, should be included in the relevant sections of Modules 4 and 5.

Bioavailability studies will not be required if there is evidence of compliance of the reproduced drug with the criteria defined in the Rules for Conducting Bioequivalence Studies of Medicinal Products in the Eurasian Economic Union.

For a replicated drug whose active substance is represented by another salt, ester or derivative of the active substance then that of the registered drug, reports of relevant preclinical and (or) clinical studies / studies of comparative bioavailability, proving the absence of changes in the pharmacokinetics, pharmacodynamics and (or) toxicity of the reproduced drug should be presented.

In case of failure to provide such evidence, this substance is considered as a new active substance.

7. Requirements for the documents of the registration dossier of the hybrid medicinal product

The registration dossier of a hybrid drug should 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, the applicant must provide brief information (up to 5 pages) that summarizes the rationales and facts used to show that the drug for which registration is filed is a hybrid product in relation to the corresponding original drug; such a summary should contain information about the preparation, the active pharmaceutical ingredient, the dosage form, the dosages, the indications for use, the method of application in comparison with the original preparation, and, if necessary, the bioavailability and bioequivalence of the drug.
In certain cases, a risk management plan may be required.
In the absence of certain elements, a justification for their absence should be provided in the relevant section.

7.2. Module 2

In the review of preclinical and clinical data, particular attention should be paid to the following elements:

• a summary of the profile of impurities of the active substance (and, if applicable, possible decomposition products formed during storage) in the series of the drug that is to be sold on the pharmaceutical market;
• updating of literary publications on the active substance within the framework of this application for registration; this requirement can be fulfilled by referring to articles in peer-reviewed journals;
• each item in the general characteristic of the medicinal product, previously not known or derived from the characteristics of the drug and / or its therapeutic group, should be
• analyzed in pre-clinical and clinical reviews / summaries and supported by evidence from published literature and / or from additional studies;

Additional information should be provided to prove that the safety and / or efficiency profiles of the claimed drug do not differ from those of the reference preparation (summary of own preclinical and (or) clinical studies).

7.3. Module 3

Module 3 should be presented in its entirety.

7.4. Modules 4 and 5

The results of preclinical and (or) clinical studies of the hybrid drug should be included in the relevant sections of Modules 4 and 5.
The order of carrying out of the additional researches necessary for reproduced and hybrid drugs or for applications for registration with extended requirements

	Options for submitting applications	Additional data required
а)	various salts / esters / complexes / their derivatives (with the same active part of the molecule)	Evidence that there is no change in the pharmacokinetics of the active part of the molecule, pharmacodynamics and / or toxicity that could significantly affect the safety / efficacy profile (otherwise it should be considered as a new active substance)
b)	Other route of administration / other dosage form (for parenteral administration, it is necessary to distinguish between intra-arterial, intravenous, intramuscular, subcutaneous and other administration methods) i) a new i) a new way of introduction  ii) other dosage form (with the same administration route)	Clinical data (safety / efficacy), pharmacokinetics, relevant preclinical data (eg, local tolerability), if applicable
c)	other dosage for the same route of administration / dosage form and indications for use	Comparative bioavailability (see Rules for Conducting Studies on the Bioequivalence of Reproduced Medicines in the Eurasian Economic Union)
d)	supra-diverticides while maintaining the dosing interval, but with a dose reduction designed to achieve a similar concentration in plasma / blood	In some cases, comparative bioavailability studies are sufficient (see Rules for bioequivalence studies of reproduced drugs in the Eurasian Economic Union)

8. Requirements for the documents of the registration dossier for drugs with well-studied medical application

For medicines whose active substance has been well studied in medical use, with proven efficacy and an acceptable level of safety (which include medicines from raw materials of natural origin (tar birch, snake venom, beekeeping products, medical leeches, bile, minerals, etc.) , vitamins and vitamin-mineral complexes, as well as medicines whose pharmacological activity determines a complex of biologically active substances of natural origin, solution (hydrogen peroxide, iodine, brilliant green, etc.), water for injection, adsorbents (activated carbon, etc.)), the following special rules should be applied.

The applicant must submit Modules 1, 2 and 3, as described in Part I of this annex.

Modules 4 and 5 in the detailed scientific bibliography should indicate preclinical and clinical characteristics.

To confirm a well-studied medical application, all the following data should be provided:

1) the factors that need to be considered when determining the well-studied medical use of the components of medications:

the time during which the active substance is used in medical practice;
quantitative aspects of the use of the active substance;
the frequency of scientific publications and the relevance of the use of the active substance in the last 5 years before submitting the application (with reference to publications in scientific sources);
consistency of scientific assessments.
To determine the well-studied use of various active substances, an estimate may be needed for different time periods. The period of time necessary to determine the well-studied medical use of the active substance must be at least 10 years in the markets of all EAEU member states. Biological medicinal products and medicines for which bioequivalence and / or clinical trials are required are not classified as drugs with well-studied use;

2) the files of drug registration dossier submitted by the applicant should include all aspects of the safety and efficacy assessment, contain or refer to a review of the relevant literature, taking into account pre- and post-registration studies and published scientific literature on the results of epidemiological studies and especially comparative epidemiological studies, all documentation, both positive and negative. Bibliographic reference to other sources of evidence (post-registration research, epidemiological studies, etc.), in addition to data on methods of control and testing, can be a proof of the safety and efficacy of the drug, provided that the drug registration dossier clearly explains and justifies the use of these sources of information;

3) it is necessary to justify why an acceptable level of safety and (or) efficacy may be considered to be valid, despite the absence of some studies;

4) in preclinical and / or clinical reviews, it is necessary to explain the significance of any data presented regarding an already registered drug different from that which proposed for registration. It is necessary to provide a justification as to whether the declared medicinal product can be considered similar to the already registered medication, despite the existing differences;

5) post-registration experience of use may contain information on the use of other drugs containing the same active substances.

6) in the event that the medicinal product has experience of application in the markets of third countries, a periodic updated report on the safety of the medicinal product is submitted for the last 5 years prior to submission of the application for registration.

9. Requirements for the registration dossier of combined medicines

For new drugs that are a combination of two or more previously known active substances in a single dosage form, a complete registration dossier (Modules 1-5) is provided, in accordance with part 1 of this annex. Module 3 includes information on the production, quality control, the manufacturer of each active substance that is part of the combination medicines. Modules 4 and 5 present the results of preclinical and clinical studies of the claimed combinations of active substances.

 

10. Requirements for the registration dossier of biosimilars (bio-like medicinal products)

To register a biosimilar (bio-like medicinal product), the data of its comparative studies with a refractory biological drug are provided. The quality, safety, efficacy and immunogenicity of the biosimilar (bio-like drug) at the production, preclinical and clinical phase of its development should be compared with the same reference biological drug in accordance with the Rules for the Study of Biological Medicines in the Eurasian Economic Union. The registration dossier of the biosimilar drug (bio-like medicinal product) is provided in accordance with the requirements of this section.

10.1. Module 1

10.1.1. In section 1.5.2. the applicant must provide brief information summarizing the reasons and facts used to show that the drug for which registration is filed is a biosimilar of the original drug. Such a generalization should contain information about the preparation, the active substance, the dosage form, the dosages, the indications for use, the method of application in comparison with the original drug.

10.1.2. In section 1.7. together with brief information on the pharmacovigilance system of the holder of the drug registration certificate, a risk management plan for the claimed biosimilarity is submitted.

10.1.3. In the absence of certain elements, a justification for their absence should be provided in the relevant section.

10.2. Module 2

In the review of quality data, preclinical and clinical data, it is also necessary to provide comparative information with the reference medication, the criteria for selecting the reference medication.
The study report or a separate official letter should confirm the selection of the reference medication in accordance with the Rules for the conduct of biological medicinal products research in the Eurasian Economic Union, as well as the following information about the reference preparation - trade name, dosage, dosage form, holder of the registration certificate, date of registration, registration certificate number, state (s) - member (s) of the EAEU, where the reference product is registered , serial number, manufacturer's name, expiration date and country of purchase. If needed - provide a recommendation of the Expert Committee on Medicines under the Eurasian Economic Commission for the selection of the reference preparation.

It is necessary to indicate the name and composition of the test drug (s), the size of the lot, the date of manufacture, and, if possible, the expiration date.

It is necessary to provide a justification for the amount of comparative preclinical and (or) clinical studies conducted, taking into account the requirements of the Rules for conducting biological drug studies in the Eurasian Economic Union. In the annex to the study report, it is necessary to add the analysis certificates for the series of reference and test drugs used in the study.

10.3. Module 3

In Module 3, the following data should be additionally submitted, taking into account the requirements of the Rules for Conducting Research on Biological Medicines in the Eurasian Economic Union:

1) confirmation of similarity of molecular and biological characteristics of biosimilar active substances and reference biological drug (data on primary structure and structures of higher order, posttranslational modifications, including, in particular, glycoforms, biological activity, purity, impurities);

2) confirmation of the similarity of the characteristics of the biosimilar drug (dosage form, quantitative and qualitative composition, dosage, method of application, storage conditions, shelf life, stability, impurity profile) and reference biological drug;

3) in the presence of differences in impurities and excipients, their potential impact on the clinical safety profile and efficacy of the biosimilar should be assessed, and the reasons of the acceptability of these differences (based on the results of one's own research or scientific literature) is provided; in the presence of differences with unknown clinical significance, especially in terms of safety, additional research is required in the pre- and post-registration period;

4) a complete description and data on the production process, starting with the development of expression constructs (systems), the original producer strain and cell banks, culture / cultivation of cells, collection, purification, additional production processes after isolation and purification of the product, filling containers for bulk product and finished dosage form, storage;

5) studies conducted during pharmaceutical development to determine and substantiate the dosage form, composition and packaging / closure system (including their integrity to prevent microbial contamination);

6) the specification of the biosimilar drug, which should reflect and regulate the important qualitative indices of the drug known for the reference biological drug (such as identification, purity, activity, molecular heterogeneity in terms of size, charge and hydrophobicity, where it is possible to determine them, degree of sialing, quantity individual polypeptide chains, glycosylation of the functional region, degree of aggregation, impurities such as protein and DNA of the host cell, etc.);

7) stability studies.

10.4. Module 4

In Module 4, the results of preclinical (non-clinical) biosimilar drug studies should be presented in comparison with the reference biological medicinal product in accordance with the requirements of the Rules for Biological Medicines Research in the Eurasian Economic Union.

10.5. Module 5

In Module 5, they are submitted in accordance with the requirements of the Rules for Biological Drugs Research in the Eurasian Economic Union:

1) the results of clinical studies of the biosimilar drug in comparison with the reference medicinal product:

pharmacokinetic studies (single-dose pharmacokinetic studies, pharmacokinetic studies with repeated administration in the presence of pharmacokinetics dependence on dose and time, pharmacokinetic comparison of the biosimilar drug and reference drug should include the study of absorption, bioavailability, clearance characteristics, i.e., clearance and / or half-life );

pharmacodynamic studies (pharmacodynamic effects should be evaluated on a suitable population and using doses from the steep portion of the dose-response curve in preclinical studies, pharmacodynamic markers should be selected depending on their clinical significance);

• comparative clinical trials, including assessment of the type, frequency and severity of adverse events / reactions; immunogenicity studies on the target group (comparison of the frequency of formation and type of antibodies formed, potential clinical consequences of the immune response for the biosimilar drug and reference medicinal product); immunogenicity should be investigated in a population of patients with the highest risk of immune response and immune unwanted reactions;
• there should be a rationale for the antibody detection strategy, including the selection, evaluation and characterization of methods, the establishment of sampling times, including pre-application, volumes, handling and storage of samples, and statistical methods for data analysis; analytical methods for determining antibodies should be validated for the intended purpose, preliminary analysis of sufficient sensitivity of the method should be carried out, neutralizing antibodies should be determined;
• the observation period for immunogenicity studies should correspond to the planned duration of treatment and the estimated time of antibody formation, and should not be less than 12 months; in case of a different study duration, a justification should be provided;
• in clinically significant cases of antibody titre formation and retention of their titre for a certain time, potential changes in the nature of the immune response and clinical consequences are required to be studied in the pre- and post-registration period;
• basic clinical data should be obtained using a medicinal product produced by the final production process, i.e. a medicinal product for which an application for registration is filed; for any deviations from these requirements, the applicant must provide a justification, and if necessary, additional studies of the comparability of the medicinal product with the final and earlier composition, in accordance with the Rules for Conducting Studies of Biological Medicines on the Territory of the Eurasian Economic Unified Energy System;

2) a risk management plan that includes a safety specification (describing the important identified and possible negative aspects of the safety of the reference drug, the class of drugs and / or biosimilars) and the biosimilar pharmacovigilance plan for the post-marketing period (describing the planned post-marketing activities and methods based on the safety data sheet , management plan and risk minimization, including information materials for patients and / or medical and pharmaceutical workers).

11. Registration dossier for applications for registration of medicinal products "in exceptional cases"

The drug registration certificate may be issued on the terms of fulfillment of certain obligations if, the applicant can confirm (substantiate) that it is impossible to provide complete data on efficiency and safety under normal conditions of use, since:

• the indications for use for which a medicinal product is intended to be used are so rare that the applicant can not reasonably expect to receive comprehensive confirmation, or
• with existing scientific data, complete information can not be provided, or
• the collection of such information will be contrary to the generally accepted principles of medical ethics.

These obligations may include the following:

• the applicant must complete a specific safety or effectiveness research program within the time period specified by the authorized agency of the EAEU Member State, the results of which should form the basis for a reassessment of the benefit / risk ratio;
• the medicinal product that is considered for registration may be dispensed only by prescription and may, in certain cases, be used only under strict medical supervision, possibly in a hospital, and in the case of radiopharmaceuticals, an authorized person;
• instructions for medical use, SmPC, registration certificate and any medical information should draw the attention of the health care provider to the fact that the available characteristics of the drug in question are inadequate in certain sections of efficacy or safety.

 

Part III. Special requirements for registration documents dossier of selected types of medicinal products

12. Biological medicinal preparations

Module 3 registration dossier of vaccines, blood products is formed taking into account their features specified in this section.

12.1. Drugs derived from plasma

For medicinal products derived from human blood or plasma, as an exception to the general requirements for Module 3 of the registration dossier, the requirements for raw materials and raw materials derived from human blood / plasma can be replaced by a master file on the plasma corresponding to this part.

12.1.1. General principles.

Within this application:

• the master file on the blood plasma is an independent document separate from the registration dossier containing all relevant detailed information on the characteristics of the whole human blood plasma used as a raw material and / or raw material in the production of subfractions or intermediate fractions, components of excipients or active substances that are some medicines or medical products;
• every center or institution, conducting fractionating / plasma-processing of a human plasma should prepare and maintain an updated set of detailed, meaningful information specified in the master file on blood plasma;
• the master file on the plasma must be submitted by the applicant or the holder of the drug registration certificate to the authorized body. If the applicant or the holder of the drug registration certificate is not the owner of the master file, the mater file must be available to the applicant or the holder of the registration certificate of the drug for submission to the authorized bodies. In any case, the applicant or the holder of the registration certificate is responsible for the medicinal product;
• if the drug registration dossier relates to the component derived from the plasma, reference should be made to the master file owner regarding the plasma used as the raw material / source material.

12.1.2. Additional requirements for the contents of the registration dossier.

The master file of the owner must contain information about the plasma used as raw material / source materials, namely:

1) The origin of the plasma
information on the centers or facilities in which blood / plasma is collected, including inspection and special permission for this activity, as well as epidemiological data on blood-borne infections in the region;
information on the centers or institutions in which the donations and plasma pools are monitored, including inspection and regulatory status;
criteria for selection / exclusion of blood / plasma donors; a description of the current system, allowing to track the path of each donation from the institution where the blood / plasma is collected, to the finished medicinal product and vice versa.
2) Plasma quality and safety
compliance with the articles (monographies) of the EAEU Pharmacopoeia, or in the absence of such articles (monographs) - in accordance with the articles (monographs) of the state pharmacopoeias of the EAEU member states or leading pharmacopoeias in accordance with the Concept;
control of collected blood / plasma and its pools for the presence of infectious agents, including information on control methods and, in the case of plasma pools, validation data of the methods used.
technical characteristics of containers for collection of blood and plasma, including information on used solutions of anticoagulants.
conditions of storage and transportation of plasma.
the procedure for storing any material and / or the quarantine period.
characteristic of the pool of plasma.
3) Description of the established system of interaction between the manufacturer of a medicinal product obtained from plasma and (or) the center or institution, fractionating and (or) processing plasma, on the one hand, and the center or institution for the collection and control of blood / plasma, on the other, as well as their agreed specifications.
Additionally, the master file on the plasma should contain a list of the drug for which it is distributed, regardless of whether these medications are registered, or are in the process of registration, or at the stage of clinical trials.

12.1.3. Examination and issuance of conclusion.

With regard to unregistered drugs, the applicant must submit to the authorized body a complete dossier, which will be accompanied by a separate master file on the plasma, if it has not been previously compiled and submitted.
Master file on the plasma is subject to examination during the drug registration process. If the results of the examination are positive, an opinion (certificate, attestation) of the EAEU is issued to the master file, which must be accompanied by an expert report. The issued certificate (certificate, attestation) is valid throughout the entire territory of the EAEU.
The master file on the plasma is subject to annual updating and re-examination.
When making changes to the master file on a plasma, it is subject to examination in accordance with the procedure for making changes.
The issued certificate (certificate, attestation) of the EAEU is adopted by the authorized bodies of the EAEU member states when implementing drug registration procedures (confirmation of registration, modification of the registration dossier) for drugs derived from human plasma / blood.

12.2. Vaccines.

For vaccines for medical use, as an exception to the general requirements for Module 3 of the registration dossier "Active pharmaceutical ingredient", the following requirements are applied based on the use of the vaccine antigen master file system.
The registration dossier for a vaccine that is not a vaccine for the prevention of human influenza should include a master vaccine antigen file for each antigen that is the active substance of this vaccine.

12.2.1. General principles.

Within this application:

the master file of the vaccine antigen considered to be a separate part of the registration dossier for the vaccine, which contains all relevant biological, pharmaceutical and chemical information regarding each of the active substances that are part of the drug. This individual part may be common to one or more monovalent and / or multivalent vaccines submitted by the same applicant or holder of the drug registration certificate;
the vaccine may contain one or more different vaccine antigens. The number of active substances in the vaccine corresponds to the number of vaccine antigens;
The combined (multivalent) vaccine contains at least two different vaccine antigens that are intended for the prevention of one or more infectious diseases;
a monovalent vaccine is a vaccine that contains one vaccine antigen designed to prevent one infectious disease.

12.2.2. Additional requirements for the contents of the registration dossier.

The master vaccine antigen file should contain the following information extracted from the relevant part (Active pharmaceutical ingredient) of Module 3 "Quality", as described in Part I of this annex.

Active substance

1. General information, including information on compliance of the article (s) (monograph (s)) of the EAEU Pharmacopoeia, or in the absence of such articles (monographs), to articles (monographies) of state pharmacopoeias of the EAEU member states or leading pharmacopoeias in accordance with the Concept.
2. Information on the manufacturer of the active substance: information on the production process, raw materials and source materials, special measures for vector-borne spongiform encephalopathies and assessment of the safety of foreign infectious agents, facilities and equipment.
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.

Examination and issuance of an opinion.

- For new vaccines that contain a new vaccine antigen, the applicant must file a complete registration dossier with the authorized body of the Member State, including all master vaccine antigen files for each vaccine antigen that is part of the new vaccine if the master vaccine antigen file is for such a vaccine antigen absent. If the results of the examination are positive, an opinion (certificate, certificate) of the EAEU is issued to the master file, which must be accompanied by an expert report. The issued certificate (certificate, certificate) is valid throughout the entire territory of the EAEU.
- The requirements referred to in the previous part of this paragraph also apply to each vaccine that consists of a new combination of vaccine antigens, regardless of whether one or more antigens are part of the vaccines that are already registered in the member states of the EAEU.
- When making changes to the master file for vaccine antigen, it is subject to examination in accordance with the procedure for making changes.
- The issued certificate (certificate, certificate) of the EAEU is adopted by the authorized bodies of the EAEU member states when implementing registration procedures (registration confirmation, modification of the registration dossier) of vaccines.

12.3. Simplified registration dossier for vaccines with well-studied medical use, the production of which was carried out in the territory of the EAEU member states until 2000

For vaccines, the vaccine antigen of which has been well studied in medical application, with proven effectiveness and an acceptable level of safety, the following special rules should be applied in the territory of the EAEU member states until the year 2000.

The applicant must submit the Module 3 as described in Part I of this Annex and Section 12.2 of Part II of this Annex.

In Modules 4 and 5, instead of reports on preclinical and clinical studies, a scientific review bibliography is presented in which preclinical and clinical characteristics should be indicated.

13. Radiopharmaceuticals and precursors

The registration dossier for the registration of radiopharmaceuticals and their precursors is submitted in accordance with the requirements of this section.

13.1. Radiopharmaceutical preparations

13.1.1. Module 3

a) In a radiopharmaceutical kit, which is supplied with a radioactive label after delivery by the manufacturer, a part of the kit intended for the transfer or binding of the radionuclide is taken for the active substance. A description of the method for producing a radiopharmaceutical kit should include detailed data on the production of the kit and data of the recommended final treatment for the production of a radioactive drug. The required radionuclide specifications should be described in accordance with, if applicable, with the general or private article (monograph) of the EAEU Pharmacopoeia, or in the absence of such articles (monographs) in accordance with the articles (monographies) of the state pharmacopoeias of the EAEU member states or the basic pharmacopeia.

In addition, all the compounds necessary for introducing the radioactive label should be described. Also describe the structure of the radioactive label.

It is necessary to analyze nuclear reactions of radionuclides.

Both the parent and daughter radionuclides of the generator are considered to be active substances.

b) It is necessary to provide information on the nature of the radionuclide, the authenticity of the isotope, possible impurities, carrier, application and specific activity.

c) The starting materials include target materials for irradiation.

d) It is necessary to consider the chemical / radiochemical purity and its relationship with biodistribution.

e) It is necessary to describe radionuclide purity, radiochemical purity and specific activity.

f) Generators require detailed test data for parent and daughter radionuclides. For generator-eluates, it is necessary to present tests of the parent radionuclides and other components of the generator system.

g) The requirement to express the content of active substances based on the mass of the active part of the molecule should be applied only to radiopharmaceutical kits. For radionuclides, radioactivity must be expressed in backward curtains, indicating the date and, if necessary, time and time zone. You must specify the type of radio activity.

h) The specification of the drug, which is a radiopharmaceutical kit, should include tests of the properties of the preparation after the introduction of the radioactive label. It is necessary to include appropriate controls on the radiochemical and radionuclide purity of the radioactive label. Any material necessary for the introduction of a radioactive label must be authenticated and quantified.

i) Stability information should be provided for isotope generators, isotope kits and radiolabeled drugs. Stability should be indicated when using radiopharmaceuticals in reusable containers.

13.1.2. Module 4
Toxicity can be associated with radiation dose. In the diagnostics - this is an undesirable consequence of the application of radiopharmaceuticals; in therapy is a desirable property, therefore, in assessing the safety and efficacy of radiopharmaceuticals, it is necessary to indicate the requirements for medicinal products and aspects of radiation dosimetry. It is necessary to document the effect of radiation on the organ / tissue. The indicator of the absorbed radiation dose should be calculated with the indication of the system of internationally recognized units of measurement used in a certain route of administration.
13.1.3. Module 5
If applicable, the results of clinical trials should be reported or rationale for their absence should be explained in literature reviews (Module 2).

13.2 Radiopharmaceutical precursors used to introduce radioactive tagss

In the case of a radiopharmaceutical precursor intended solely for the introduction of radioactive tags, it is firstly necessary to provide information about possible consequences of the inefficient introduction of radioactive labels or the dissociation in vivo of a radiolabeled conjugate, i. e. questions related to the action that a free radionuclide has on patients. In addition, it is also necessary to provide relevant information on risk factors, i.e. radioactive effects on hospital staff and the environment.

In particular, it is necessary to provide the following information:

13.2.1. Module 3

The provisions of Module 3 should be applied to the registration of radiopharmaceutical precursors, as described above (paragraphs a - i), if applicable.

13.2.2. Module 4

With regard to toxicity in a single and repeated administration, it is necessary to present the results of preclinical studies conducted in accordance with the rules of good laboratory practice.
Studies on the mutagenicity of radionuclides are not considered applicable in this particular case.

It is necessary to provide information on the chemical toxicity and distribution of the corresponding "cold" (radioactive substances that do not contain radioactive substances) nuclide.

13.2.3. Module 5

Clinical information obtained from clinical studies using a precursor alone is not considered significant in the case of a radiopharmaceutical precursor intended solely for the introduction of a radioactive label.

It is necessary to provide information that confirms the clinical effectiveness of the radiopharmaceutical precursor when attached to the molecules of the corresponding carrier.

14. Homeopathic medicines

14.1. Module 3.

a) Terminology.

The scientific name in Latin of the homeopathic pharmaceutical substance described in the drug registration dossier should correspond to the scientific name in Latin of the monograph of the EAEU Pharmacopoeia or, in the absence thereof, the homeopathic pharmacopoeia of the EAEU member states, or the homeopathic pharmacopoeia of Germany, the pharmacopoeia of France and the European Pharmacopoeia.

b) Control of raw materials.

The materials of the registration dossier should include the documents confirming the conformity of the quality of all components of the preparation, including homeopathic pharmaceutical substance and auxiliary substances, to the requirements of references to monographs or normative documentation given in the "Composition" section. For a homoeopathic pharmaceutical substance, monographs of the pharmacopoeia of the EAEU (if available) or of the EAEU member states or the monograph of the homeopathic pharmacopoeia of Germany, or the monograph of France or the European Pharmacopoeia; for auxiliary components - normative documentation or monographs of pharmacopoeias.

The main quality requirements should apply not only to all raw materials and source materials, but also to intermediate products (dilutions of the substance), to the final dilution that is introduced into the medicinal product. In the case of the use of a homeopathic pharmaceutical substance containing a potent or toxic active ingredient, the content of such an active ingredient must be determined in a suitable manner and appropriately regulated (for example, by double-rationing the content of such an active substance or by testing the fourth decimal dilution). As a rule, breeding above the D4 decimal scale and the dilution of the centenary scale does not allow such an assessment.

If the homeopathic pharmaceutical substance (s) is used for the production of a homeopathic medicinal product, they are prepared in accordance with the methods and methods described in the relevant monograph of the EAEU pharmacopoeia or (if none), in the monograph of pharmacopoeias of the states - members of the EAEU or the monograph of the homeopathic pharmacopoeia of Germany, the monograph of France or the European Pharmacopoeia, and indicate the scale and the degree of dilution.

c) Control tests of the drug.

The main quality requirements should be applied to homeopathic medicinal products, any exception should be justified to the applicant.

If a homeopathic pharmaceutical substance is used to manufacture a homeopathic medicinal product, containing a potentially hazardous or toxic active substance, tests should be carried out to determine the authenticity and quantification of these substances in the homeopathic medicinal product (if applicable). If there is a substantiation about the impossibility of quantitative determination and (or) identification of all toxicologically significant components, for example, due to the degree of dilution in the medicinal product, the quality must be confirmed by full validation of the production process and the breeding process. In case if for production of homeopathic medicinal product is used homeopathic pharmaceutical substance containing no potent or poisonous active substance, tests should be conducted to establish the authenticity and quantitative determination of substances according to monographs on homeopathic pharmaceutical substances of concrete names (if applicable).

d) Stability tests.

It is necessary to confirm the stability of the drug. The test data for the stability of the original homeopathic 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, the stability test data of the dosage form can be considered.

14.2. Module 4.

Data from preclinical toxicity studies.

The absence of any information should be justified, for example, to justify how an acceptable level of safety can be confirmed in the absence of some studies.

For new homeopathic medicinal products (matrix infusions, triturations and other components) not mentioned in pharmacopoeias and monographs: toxicological studies, the rationale for the selection of various dosages and the subsequent data of a clinical trial

14.3. Module 5.

Data of clinical trials, applications in the post-registration period (if available).

The absence of any information should be justified, for example, to justify how an acceptable profile of efficiency and safety can be confirmed in the absence of some studies.

For homoeopathic medicinal products (matrix infusions, triturations and other components) not mentioned in pharmacopoeias and monographs, it is compulsory to submit clinical research data (in accordance with the requirements of this annex), justification of the selection of various dosages.

For homoeopathic drugs having long-term experience (not less than 10 years from the date of the first systematic and documented use in all EAEU member states) and included in pharmacopoeias: a review of the scientific literature data on the efficacy and safety of the homeopathic medicinal product in the claimed scope is provided.

In the SmPC and IFU of the medicinal product, the indication: "homeopathic medicinal product" is included.

14.4. Simplified registration dossier for homeopathic medicinal products.

To register homeopathic medicines that satisfy all of the following conditions, a simplified dossier is provided:

a) intended for ingestion or for external, local, inhalation use;

b) a specific therapeutic indication for use is not given on the drug package, SmPC or IFU;

c) the degree of dilution is sufficient to guarantee the safety of the medicinal product, in particular the medicinal product contains no more than 1/10 000 parts of homeopathic substance (matrix homeopathic tincture) or contains no more than 1/100 of the minimum dose used in allopathy in respect of active substances, the presence of which in the drug requires prescription, Evidence of therapeutic efficacy for these homeopathic medicines is not required. The leave category of such homeopathic medicinal products is established at the time of registration.

An application for a special, simplified registration procedure can cover a series of medications derived from the same homoeopathic pharmaceutical substance or several homeopathic pharmaceutical substances combined by nature (for example, animal, mineral or vegetable origin).

In order to confirm the pharmaceutical quality and uniformity of the drug from series to series, the application is accompanied by a registration dossier with the following documents:

• the scientific name in Latin of the homeopathic pharmaceutical substance (s) given in the pharmacopeia, indicating the scale and degree of dilution, data on the routes of administration, dosage forms and the degree of dilution to be recorded;
• one or more mock-ups of consumer and primary packaging, as well as SMPC and instructions for medical use (leaflet) of homeopathic medicinal products for simplified registration;
• dossier describing the way of obtaining and controlling homeopathic pharmaceutical (their) substance (s), raw materials or raw materials, the rationale for his (their) homeopathic use on the basis of the relevant bibliography;
• description of production and control for each dosage form, description of the scale, method of dilution (potentiation);
• a license for the production of medicinal products and a document confirming compliance with the proper production practice of the EAEU;
• copies of certificates of registration of a medicinal product under a simplified procedure received in other countries;
• data on the stability of homeopathic medicinal product or homeopathic medicinal preparations.

15. Herbal medicinal preparations

The registration dossier for the registration of herbal drugs is submitted in accordance with the requirements of this section.

15.1. Module 3.

The provisions of Module 3, including compliance with the pharmacopoeial articles (monographs) of the EAEU Pharmacopoeia or the Pharmacopoeia of the Member States of the EAEU, should be applied when registering herbal medicines. It is necessary to take into account available scientific information at the time of application.

15.1.1. Substances of plant origin.

Within the framework of this appendix, the term "pharmaceutical substance of plant origin" is considered a more general term, combining the terms "medicinal plant material" and "product from medicinal plant material".

For the pharmaceutical substance of plant origin obtained after grinding medicinal plant raw materials, it is necessary to indicate the binomial scientific name of the producing plant: generic and species, variety and author) in Latin, chemotype (if necessary), source of origin (wild or cultivated), morphological group of the producer plant, the name (definition) of a substance of vegetable origin.
For the pharmaceutical substance of vegetable origin, obtained after treatment of medicinal plant material by various methods (extraction, distillation, spinning, fractionation, purification, concentration, fermentation, etc.), it is necessary to specify the binomial scientific name of the producing plant: generic and species, variety and author) on Latin name, chemotype (if necessary), source of origin (wild or cultivated), morphological group of the producing plant, name (definition) substances of plant origin.

The "Structure" section for a pharmaceutical substance of plant origin obtained after grinding medicinal plant raw materials includes an indication of its category (whole, crushed, powder); for a pharmaceutical substance of plant origin obtained after processing medicinal plants in different ways (extraction, distillation, spinning, fractionation, purification, concentration, fermentation, etc.) includes an indication of the aggregate / physical state (for example: extract dry / thick / liquid), description of components with known therapeutic action or markers (molecular formula, relative molecular weight, structural formula, including relative and absolute spatial structure, molecular formula and relative molecular weight), as well as other components.

The section on the manufacturer of medicinal plant raw materials must contain information: name, address and responsibility of each supplier, each production site or laboratory involved in harvesting / manufacturing and quality control of herbal medicinal raw materials.

The section on the manufacturer of a product from medicinal plant raw materials should contain information: the name, address and responsibility of each supplier, each production site or laboratory involved in the production and quality control of a product from herbal medicinal raw materials.

The section "Description of the production process and its control" for medicinal plant raw materials should contain information on the process of harvesting wild or cultivated medicinal plant material (the geographical source of the medicinal plant, description of the cultivation process) and methods for its further processing (collection, drying) and storage conditions. For a product from medicinal plant raw materials, it is necessary to provide information on: the production process for obtaining the product, including processing description, solvents and reagents, purification steps and, if applicable, standardization.

With regard to the development of the production process, it is necessary to present a summary describing the development of plant (s) substance (s). With regard to the development of the production process of a product from herbal raw materials, a summary should be provided describing the development of the product, taking into account the proposed route of administration of the herbal preparation and its medical application. It is necessary to consider the results of a comparative phyto-chemical analysis of medicinal plant material and a product from medicinal plant raw materials, if necessary, using bibliographic data.

When describing the structure and other characteristics of herbal medicinal raw materials, it is necessary to provide information on botanical, macroscopic, microscopic, phytochemical characteristics and biological activity, if necessary.

When describing the composition and other characteristics of the product from herbal medicinal raw materials, it is necessary to provide information on the phyto- and physico-chemical characteristics and biological activity of plant products, if necessary.

Specification should be provided for herbal medicinal raw materials and products from herbal medicinal raw materials, if applicable.

It is necessary to indicate the analytical methods used for testing the pharmaceutical substance of plant origin, to report on their validation (if they are not pharmacopeial), including experimental data for the analytical techniques used for the tests.

The data of the series analysis should be presented as a description of the series and results of the series analyzes for a plant-based substance, including those for pharmacopeia substances.
It is necessary to provide a justification for the specifications of the substance of plant origin, if applicable.

Information should be provided on standard samples and materials used for testing substances of plant origin.

If a monograph on the substance of plant origin is included in the European Pharmacopeia, the applicant may submit a certificate of conformity issued by the European Directorate for the Quality of Medicines (where available).

15.1.2. Herbal drugs composition.

Concerning the development of the composition, it is necessary to present a summary describing the development of a medicinal plant preparation, taking into account the proposed route of administration and use.

It is necessary to analyze the data on the phytochemical composition of the declared herbal preparation, and the data given in bibliographic scientific sources.

The section "Description of the production process and its control" for the medicinal plant preparation should contain information on the production process for the preparation of the preparation, including treatment description, solvents and reagents, auxiliary substances, purification steps and, if applicable, standardization.

15.1.3 Modules 4 and 5.

Results of preclinical (toxicological and pharmacological) and clinical studies;

In the case of combined herbal preparations (including combinations with vitamins and / or minerals), if the individual components of the combination are not sufficiently studied, data for each individual component of the combination should be provided.

15.2. Simplified registration dossier of herbal medicinal preparations.

A simplified registration dossier for the registration of herbal medicinal preparations is provided for herbal drugs in medicinal forms of tincture, extracts, etc., as well as crushed or powdered, cut-pressed parts of the plant and other preparations, subject to the following requirements:

a) indications for use correspond to the well-known properties and composition of the medicinal plant and are intended for use without control by the doctor for the purpose of prevention or treatment;

b) in certain general characteristics of the drug, the methods of administration and doses;

c) intended for ingestion, for external, local and (or) inhalation use;

d) the safety of the use of herbal medicinal product is based on long-term experience (at least 10 years from the date of the first systematic and documented use of medicinal herbal preparation in all the Member States of the EAEU);

e) the labeling and instructions for medical use (leaflet-liner) of the herbal preparation must contain indications that:

- the preparation is a medicinal herbal preparation for use for the specified purpose, based on the experience of prolonged use; and
- the consumer should consult a physician or a qualified medical professional if symptoms persist when using the drug or if there are undesirable reactions not indicated in the medical instructions (leaflet).

If there are vitamins or minerals in the herbal preparation, a simplified registration procedure is carried out provided that the evidence is presented proving that the action of vitamins or minerals is an auxiliary action of plant active ingredients in relation to declared indications for use.

15.2.1. Module 2.

Bibliographic data or the conclusion of a specialist who prepared sections 2.4-2.4 of the module that the herbal medicinal product in question or the corresponding preparation was used for at least 10 years from the date of the first systematic and documented use of herbal medicines in all EAEU member states.

15.2.2. List of documents of the simplified registration dossier.

In order to confirm the pharmaceutical quality and uniformity of the drug from series to series, the application is accompanied by a registration dossier consisting of modules 1-3 in accordance with Appendix 4-1. Instead of modules 4-5, copies of bibliographic sources and data on which the surveys prepared by the specialist are based in sections 2.4-2.5 of module 2 of the registration dossier are presented.

16. Orphan drugs (drugs designed to treat rare diseases)

In the case of orphan drugs, the main provisions of Part II (exceptional circumstances) may be applied. The applicant must justify in pre-clinical and clinical summaries the reasons for which it is impossible to provide complete information and provide a justification for the benefit / risk relationship for the orphan drugs under consideration.

Part IV. High-tech medicinal products

17.1. Introduction

For registration dossiers of high-technology drugs, the format requirements (Module 1, 2, 3, 4 and 5) described in Part I of this annex must be observed.

The technical requirements for Modules 3, 4 and 5 should be applied to high-tech biological drugs, as described in Part I of this annex. 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 in Part I apply to high-tech medicinal products.

In view of the specific nature of high-tech medicines, a risk-based approach can be applied to determine the amount of information required and the quality requirements, preclinical and clinical studies, for inclusion in the registration dossier in accordance with applicable guidelines of the EAEU or, in their absence, in accordance with the guidelines of the member states of the EAEU.

Risk analysis may include the entire development. Risk factors that may be considered include: the origin of cells (autologous, allogeneic, xenogeneic), the ability to proliferate and / or differentiate, and the ability to induce an immune response, manipulation of cells, a combination of cells with bioactive molecules or medical products, the nature of the gene therapeutic drug preparation, the ability to replicate viruses or multiply microorganisms used in vivo, the degree of integration of nucleic acid or gene sequences into the genome, continuity of operation (existence), the risk of oncogenicity and the mode of administration or use.

Relevant existing non-clinical and clinical data or experience with other related high-technology medicines may also be considered in risk analysis.

Any deviation from the requirements of this annex should be scientifically justified in Module 2 dossier. If a risk analysis is carried out as it described above, it should be included and described in Module 2. In this case, it is necessary to consider the methodology used, the nature of the risks identified and the impact of the results of the risk-based approach to the drug development and evaluation program. It is also necessary to describe any deviations from the requirements of this application due to the results of the risk analysis.

17.2. Definitions

17.2.1. Gene therapy drugs.

The gene therapy drug is a biological medicinal product:

(a) containing an active substance comprising or consisting of a recombinant nucleic acid used or administered to a human for the purpose of regulating, restoring, replacing, adding or removing a genetic sequence;
(b) the therapeutic, prophylactic or diagnostic effects of which are directly attributable to the sequence of the recombinant nucleic acid it contains, or to the product of the genetic expression of that sequence.

Gene therapy drugs do not include vaccines against infectious diseases.

17.2.2. Medicines based on somatic cells

A medicinal preparation based on somatic cells is a biological medicinal product:

(a) containing or consisting of cells or tissues that have undergone significant manipulation, such that their biological characteristics, physiological functions or structural properties significant for clinical use have been altered; or consisting of cells or tissues that are not intended for use in order to perform the same basic functions in the recipient and donor;
(b) used in humans for the purpose of treating, preventing or diagnosing a disease by means of the pharmacological, immunological or metabolic effects of its cells or tissues.

Within the framework of point (a), manipulations such as cutting, grinding, shaping, centrifugation, treatment with solutions of antibiotics or antiseptics, sterilization, irradiation, cell separation, concentration or purification, filtration, lyophilization, freezing, cryopreservation, vitrification, are not considered significant manipulations.

17.3. Special requirements for the Module 3

17.3.1. Special requirements for all high-tech medicines.

It is necessary to provide a description of the traceability system that the applicant undertakes to establish and maintain in order to trace the sources of origin, production, packaging, storage, transportation and delivery to the medical organization of a separate medicinal product and its raw materials and raw materials, including all substances that contacted the contained in it by cells or tissues.

The traceability system must complement and harmonize with the requirements for traceability systems, the member states of the EAEU, relative to human cells and tissues.

17.3.2. Special requirements for gene therapy drugs.

17.3.2.1. Introduction: medicinal product, active substance and starting materials.

17.3.2.1.1. Gene therapeutic drugs containing a sequence (s) of recombinant nucleic acids or a genetically modified microorganism (s) or virus (s).

The drug should consist of a nucleic acid sequence (s) or genetically modified microorganism (s) or virus (s), and be packaged in a primary packaging for medical use. A medicinal preparation can be combined with a medical product.

The active substance must consist of a nucleic acid sequence (s) or a genetically modified microorganism (s) or virus (s).

17.3.2.1.2. Gene therapy products containing genetically modified cells.

The drug should consist of genetically modified cells, and be packaged in a primary package for medical use. A medicinal preparation can be combined with a medical product.

The active substance should consist of cells genetically modified by one of the products described 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 main bank (seed) of the viral or plasmid vector used to transfect the recipient cells (packing cells) and the main bank of the cell line of the recipient (the cell packing line).

17.3.2.1.4. For products consisting of plasmids, non-viral vectors and genetically modified organism (s) other than viruses and viral vectors, the starting materials are the components used to produce the producer cells: plasmids, bacterial host cells and the main bank of recombinant microbial cells.

17.3.2.1.5. For genetically modified cells, the starting materials are the components used to produce genetically modified cells, i. E. source materials for vector production, vector and human and animal cells. The principles of good manufacturing practices should be applied starting with the system of banks used to produce the vector and then to the finished product.

17.3.2.2. Special requirements.

In addition to the requirements set out in Section 3.2.1 and 3.2.2 of Part I of this annex, the following requirements shall apply:

a) Information should be provided on all raw materials used for the production of the active substance, including products necessary for the genetic modification of human and animal cells and, if necessary, subsequent cultivation and conservation of genetically modified cells, taking into account the possible absence of purification steps;
b) for products containing microorganisms (including viruses), it is necessary to provide data on genetic modification, sequencing, attenuation of microorganisms, tropism for certain types of tissues and cells, the dependence of microorganism properties on the cell cycle, pathogenicity and characteristics of the parental strain;
c) it is necessary to describe in the relevant sections of the dossier production and related impurities and, in particular, contaminating agents in the form of replication-capable viruses, if the vector must be incapable of replication;
d) for plasmids, it is necessary to quantify various forms of plasmids throughout the shelf life of the product;
e) for genetically modified cells, it is necessary to test cell characteristics before and after genetic modification, and before and after any subsequent freezing / storage procedure.

For genetically modified cells, in addition to certain requirements for gene therapy drugs, quality requirements for drugs based on somatic cells and tissue engineering products should be applied (see Section 17.3.3.).

17.3.3. Special requirements for somatotherapeutic drugs and tissue engineering preparations.

17.3.3.1. Introduction: medicinal product, pharmaceutical substance and starting materials (substances).

The medicinal preparation must consist of a pharmaceutical substance enclosed in a primary package for the purpose of the proposed medical use, and in its final combination, if it is a combined high-tech medicinal product.

The pharmaceutical substance must consist of cells and (or) tissues subjected to engineering.

Additional substances (for example, scaffolds, matrices, products, biomaterials, biomolecules and (or) other components) that are combined with the processed cells, with which they form a single whole, are the starting materials, even if they are not of biological origin.

Materials used in the manufacture of a pharmaceutical substance (for example, a nutrient medium, growth factors) that are not intended to be included as a component of a pharmaceutical substance are raw materials.

17.3.3.2. Special requirements.

In addition to the requirements described in sections 3.2.1 and 3.2.2 of Part I of this Annex, the following requirements apply:

17.3.3.2.1. Source materials.

(a) A summary of the receipt, preparation and testing of human tissues and cells used as starting materials should be provided. It is necessary to provide a justification if unhealthy cells or tissues (for example, cancer cells) were used as starting materials.
(b) If allogeneic cell populations have been pooled, it is necessary to describe the pooling strategy and take measures to ensure tracking.
(c) When validating the production process, the description of the properties
pharmaceutical substance and drug,
analytical techniques used in the development, specification and determination of stability, it is necessary to take into account the potential variability due to the use of human and animal tissues and cells.
(d) With respect to xenogenic cellular medicinal products
(eg geographical origin, livestock farming, age), special eligibility criteria, measures for preventing and monitoring infections in animal donors, testing animals for infectious agents, including vertically transmitted microorganisms and viruses, and confirmations suitability of the conditions of animal maintenance.
(e) With respect to cellular medications derived from genetically modified animals, it is necessary to describe the specific properties of cells due to their genetic modification. It is necessary to provide a detailed description of the method of creating and describing the properties of transgenic animals.
(e) For genetically modified cells, the requirements described in Section 17.3.2 should also be considered.
(g) It is necessary to describe and justify the test conditions for all additional substances (frameworks, matrices, products, biomaterials, biomolecules and (or) other components) that were combined with cells subjected to engineering.

For frameworks, matrices and products falling within the definition of a medical device or an active implantable medical device, the information listed in section 17.3.4, required for the examination of combination medicines for advanced therapy, should be provided.

17.3.3.2.2. Manufacturing process

(a) In order to ensure the uniformity of series and production process, the functional integrity of cells during production and transport (up to the point of application or introduction) and the proper state of differentiation, it is necessary to validate the production process.
(b) If the cells are directly grown inside or on a matrix, framework or article, it is necessary to provide information about the validation of the process of obtaining a cell culture in terms of cell growth, the function and integrity of such a combination.

17.3.3.2.3. Strategy description of properties and quality control.

(a) Information should be provided on the description of the properties of the cell population or cell mixture from the point of view of their authenticity, purity (eg, the presence of extraneous microbial agents or cellular contaminants), viability, activity, karyology, tumorigenicity and suitability for the proposed medical use. It is necessary to confirm the genetic stability of cells.
(b) It is necessary to provide qualitative and, if possible, quantitative information on production and related impurities, as well as information on all materials that may lead to the formation of degradation products during production. It is necessary to justify the degree of study of impurities.
(c) It should be justified that certain tests of the issuing quality control with a pharmaceutical substance or drug can not be made, but this is possible with key intermediate products and / or within the framework of internal control.
(d) If biologically active molecules (for example, growth factors, cytokines) are contained as components of cellular medicinal products, their influence and interaction with other components of the pharmaceutical substance must be described.
(e) If the three-dimensional structure is part of the intended function, the state of differentiation, the structural and functional organization of the cells and, if applicable, the resulting extracellular matrix, should become part of the description of the properties of such cellular medications. If necessary, a description of the physico-chemical properties should complement the preclinical studies.

17.3.3.2.4. Excipients.

For the excipients used in somatotherapeutic drugs and tissue engineering preparations (for example, transport medium components), the requirements for the new excipients listed in Part I of this Annex apply, if there is no data on the interaction between cells or tissues and excipients.

17.3.3.2.5. Research on development.

When describing the development program, it is necessary to present a rationale for the choice of materials and processes. In particular, it is necessary to analyze the integrity of the population of cells 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 significant and specific for the pharmaceutical substance and / or the finished medicinal product.

17.3.4. Special requirements for high-technology medicines containing medical products

17.3.4.1. High-tech medicinal products containing medical products.

It is necessary to provide a description of the physical properties and effect of the drug and a description of the methods of its construction.

It is necessary to describe the interaction and compatibility between genes, cells and (or) tissues on the one hand and structural components on the other.

17.3.4.2. Combined high-tech medications.

By "combined high-tech medicinal product" is meant a high-tech drug that meets the following conditions:- it should include one or more medical products as part of the preparation in determining the EAEU legislation on medical devices or one or more active implantable medical devices in determining the EAEU legislation on medical devices and

- its cellular or tissue part should contain viable cells or tissues or
- its cellular or tissue part containing non-viable cells or tissues, must have the ability in the human body to exert an action that can be considered as primary in relation to the said products.

To the cellular or tissue part of the combined high-tech medicinal product, special requirements are imposed for somatotherapeutic drugs and tissue engineering products, presented in Section 17.3.3, if the cells have been genetically modified, special requirements for gene therapy drugs are presented in Section 17.3.2.

A medical device or an active implantable medical device may be an integral part of a pharmaceutical substance. If a medical device or an active implantable medical device is combined with cells during the manufacture, use or administration of a medicinal product, they are recognized as an integral part of the finished medicinal product.

It is necessary to provide information relating to a medical device or an active implantable medical device (which is an integral part of a pharmaceutical substance or medicinal product) necessary for the examination of combined high-tech medicinal products. Such information includes:

(a) information on the choice and intended function of the medical device or implantable medical device and the confirmation of the compatibility of the product with other components of the preparation;
(b) confirmation of the compliance of the medical device with the key requirements established by the EAEU legislation on medical devices or the compliance of the active implant with key requirements established by the EAEU legislation on medical devices;
(c) if applicable, confirmation of compliance of the medical device or implantable medical device with the requirements for transmissible spongiform encephalopathies;
(d) if applicable, the results of any evaluation of a medical device or active implantable medical device by a notified body in accordance with the EAEU legislation on medical devices.

The notified person who conducted the assessment referred to in paragraph "d" of this section shall, at the request of the authorized body conducting the examination of the application, submit all information related to the results of the evaluation in accordance with the EAEU legislation on medical devices. These may include information and documents contained in the conformity assessment of the application in question, if necessary for the purpose of studying a combined high-tech medicinal product as a whole.

17.4. Special requirements for the Module 4

17.4.1. Special requirements for all high-tech drugs.

In view of the unique and diverse structural and biological properties of high-technology drugs, the requirements of Module 4 of this Annex for pharmacological and toxicological studies of medicinal products are not always applicable. The technical requirements of sections 17.4.1, 17.4.2 and 17.4.3 explain how to comply with the requirements of Part I of this Annex for high-tech medicinal products. If appropriate, taking into account the specifics of high-tech medicinal products, additional requirements are established for them.

In the pre-clinical review, it is necessary to provide a scientific justification and analysis of preclinical development and selection criteria for the relevant animal species and models (in vitro and in vivo). Selected animal models can be immunocompromised, knockout, humanized or transgenic animals. Consideration should be given to the possibility of using homologous models (for example, the analysis of mouse cells in mice) or models that mimic the disease, especially in studies of immunogenicity and immunotoxicity.

In addition to the requirements of Part I, it is necessary to provide data on the safety, suitability and biocompatibility of all structural components (eg matrices, frameworks and products) and any additional substances (eg cell products, biomolecules, biomaterials and chemicals) contained in the medicinal product. It is necessary to take into account their physical, mechanical, chemical and biological properties.

17.4.2. Specific requirements for gene therapy drugs.

To determine the scope and types of preclinical studies necessary for the proper description of preclinical safety, the design and type of the gene therapy drug should be considered.

17.4.2.1. Pharmacology.

(a) The results of in vitro and in vivo studies of the effects relating to the declared indication (i.e. pharmacodynamic studies of the mechanism of action) should be presented in which models and suitable animal species are used to confirm that the nucleic acid sequence reaches the target organ or cells) and provides the necessary function (the degree of expression and functional activity). It is necessary to describe the duration of the function of the nucleic acid sequence and the proposed dosage regimen in clinical trials.
(b) Selectivity of the target. If the gene therapy drug should have selectivity or functionality limited by the target, it is necessary to present the results of studies confirming the specificity and duration of the functionality and activity of the target cells and tissues.

17.4.2.2. Pharmacokinetics.

(a) In biodistribution studies, it is necessary to study persistence, clearance and mobilization. In addition, they need to clarify the risk of generative transmission.
(b) If there is no rationale based on the type of medicinal product in the registration dossier, it is necessary to present the results of the dissemination and transmission risk studies to third parties, as well as the results of the environmental risk assessment.

17.4.2.3. Toxicology.

(a) The toxicity of the prepared
gene therapy drug. In addition, depending on the type of drug, it is necessary to conduct a separate test of the pharmaceutical substance and excipients taking into account the in vivo effect of the expression products of the nucleic acid sequence not designed to evaluate their physiological function.
(b) It is allowed to combine toxicity studies with a single injection with pharmacological safety studies and pharmacokinetic studies, for example, to study persistence.
(c) If repeated administration of the drug to a human is contemplated, it is necessary to present the results of toxicity studies with repeated administration. The mode and mode of administration should be consistent with those in clinical use. If a single administration may result in prolonged functionality of the nucleic acid sequence in a human, toxicity studies may be required for repeated administration. Depending on the persistence of the gene therapy drug and the expected potential risks, the duration of the study may exceed standard toxicological studies. It is necessary to provide a justification for the duration of the research.
(d) Genotoxicity needs to be studied. However, standard genotoxicity studies should only be carried out if a particular impurity or component of the delivery system is tested.
(e) Carcinogenicity should be studied. Standard lifelong carcinogenicity studies in rats are not required. However, depending on the type of drug, the tumorigenic potential needs to be studied in suitable in vivo / in vitro models.
(f) Reproductive and ontogenetic toxicity. If the registration dossier lacks an appropriate rationale based on the type of drug in question, it is necessary to present the results of studies on the study of fertility and the overall reproductive function. It is necessary to present the results of studying embryo-fetal and perinatal toxicity, generative transmission.
(g) Additional toxicology studies.

- Integration Studies. For all gene therapy drugs, it is necessary to present the results of studies of their integration if the lack of such results is not scientifically justified, for example, because there is no penetration of the nucleic acid sequences into the nucleus of the cell. If, based on the results of biodistribution studies, the risk of generative transmission is detected, in relation to gene therapy drugs, presumably not capable of integration, it is necessary to conduct integration studies.
- Immunogenicity and immunotoxicity. Potential immunogenic and immunotoxic effects should be investigated.

17.4.3. Specific requirements for somatotherapeutic drugs on the basis of somatic cells and preparations of tissue engineering.

17.4.3.1. Pharmacology.

(a) In order to confirm the mechanism of action, it is necessary to carry out appropriate studies of primary pharmacology. It is necessary to study the interaction of cellular preparations with surrounding tissues.
(b) The amount of medicinal product necessary to achieve the desired effect / effective dose and, depending on its type, the dosing regimen.
(c) In order to evaluate potential physiological effects that are not related to the therapeutic effect of a somatotherapeutic drug or a tissue engineering preparation or additional substances, it is necessary to present the results of a secondary pharmacology study because, in addition to the necessary proteins, biologically active molecules can be formed, or the necessary proteins may have unwanted targets.

17.4.3.2. Pharmacokinetics.

(a) Standard pharmacokinetic studies to study absorption, distribution, metabolism and excretion are not required. However, if there is no proper justification based on the type of drug under consideration in the registration dossier, it is necessary to study parameters such as viability, longevity, distribution, growth, differentiation and migration.
(b) With respect to somatotherapeutic drugs and tissue engineering products that produce active biomolecules on a continuous basis, it is necessary to study the distribution, duration and volume of expression of such molecules.

17.4.3.3. Toxicology.

(a) The toxicity of the finished medicinal product must be studied. It is necessary to consider the possibility of a separate study of the pharmaceutical substance, auxiliary substances, additional substances and all industrial impurities.
(b) The duration of the observations may exceed those in standard toxicological studies, so the expected life cycle of the drug, as well as its pharmacodynamic and pharmacokinetic properties, should be taken into account. It is necessary to provide a justification for the duration of the research.
(c) Standard carcinogenicity studies
and genotoxicity is not required, except for the tumorigenic potential of the finished drug.
(d) Immunogenic and immunotoxic potential must be studied.
(e) For cellular medicines containing animal cells, the safety issues associated with them, such as the risk of transmission of xenogenic pathogens to humans, need to be studied.

17.5. Special requirements for Module 5

17.5.1. Special requirements for high-tech medicinal products.

17.5.1.1. The special requirements of this section are additional to those presented in Module 5 of Part I of this Annex.

17.5.1.2. If for clinical use high-tech drugs require special supportive therapy or surgical procedures, the whole complex of therapeutic measures should be studied as a single whole. It is necessary to provide information on standardization and optimization of such procedures during clinical development.

If medical products used during surgical procedures for use, implantation, or administration high-tech medicinal product may affect the effectiveness and safety of the latter, it is necessary to provide information about such products.

It is necessary to provide a separate analysis aimed at assessing the application, implantation, administration and follow-up. If necessary, a plan for the training of medical personnel in the procedures for use, application, implantation and administration should be provided.

17.5.1.3. Considering that due to the properties of high-tech drugs during the clinical development process of their production may undergo changes, additional studies may be needed that confirm comparability.

17.5.1.4. In the course of clinical development, it is necessary to study the risks posed by potential infectious agents or the use of material obtained from animal sources and describe measures aimed at reducing such risks.

17.5.1.5. With the help of studies on the selection of a dose, it is necessary to determine the dose and dosage regimen.

17.5.1.6. Efficacy according to the declared indications should be confirmed by appropriate results of clinical studies in which clinically relevant endpoints were used for the intended application. In certain clinical conditions, it may be necessary to confirm long-term effectiveness. It is necessary to present a strategy for assessing long-term effectiveness

17.5.1.7. In terms of risk management, it is necessary to provide a strategy for long-term monitoring of safety and efficiency.

17.5.1.8. Safety and efficiency studies combined drugs for advanced therapy should be planned and carried out on the whole combined preparation.

17.5.2. Specific requirements for gene therapy drugs.

17.5.2.1. Pharmacokinetic studies in humans.

In pharmacokinetic studies in humans, the following should be considered:

(1) Shedding studies aimed at studying the excretion of gene therapy drugs;
(2) biodistribution studies;
(3) pharmacokinetic studies of the drug and gene expression products (eg, expressed proteins or genomic signatures).

17.5.2.2. Pharmacodynamic studies in humans.

In pharmacodynamic studies, it is necessary to study the expression and functions of the nucleic acid sequence after administration of the gene therapy drug.

17.5.2.3. Security Studies.

In security studies, the following should be considered:

(1) the emergence of vectors capable of replication;
(2) the emergence of new strains;
(3) reassortment of existing genomic sequences;
(4) tumor proliferation due to insertion mutagenesis.

17.5.3. Specific requirements for medicines based on somatic cells.

17.5.3.1. Medicines based on somatic cells, the mechanism of action of which is based on the production of certain active biological molecules.

If the mechanism of action of somatotherapeutic drugs is the production of certain active biomolecules (s), it is necessary, if possible, to describe the pharmacokinetic properties (especially the distribution, duration and extent of expression) of such molecules.

17.5.3.2. Biological distribution, persistence and long-term engraftment of components of somatotherapeutic drugs.

In the course of clinical development, it is necessary to study the biodistribution, persistence and long-term engraftment of components of a somatotherapeutic drug.

17.5.3.3. Security Studies.

In security studies, the following should be considered:

(1) distribution and engraftment after administration;
(2) ectopic engraftment;
(3) oncogenic transformation and compliance with the properties of the corresponding cell / tissue line.

17.5.4. Specific requirements for tissue injection products.

17.5.4.1. Pharmacokinetic studies.

If standard pharmacokinetic studies for tissue engineering preparations are not significant, then in the course of clinical development it is necessary to study the biodistribution, persistence and degradation of their components.

17.5.4.2. Pharmacodynamic studies.

The design of pharmacodynamic studies should be based on the characteristics of tissue engineering preparations. It is necessary to provide evidence of the "proof of concept" and the kinetics of the drug required to achieve the expected regeneration, repair, or replacement. It is necessary to take into account the appropriate pharmacodynamic markers associated with the function and structure under consideration.

17.5.4.3. Security Studies.

Follow the requirements of section 17.5.3.3.