23 May 2023

Marketing Authorizations Holders for Medicinal Products and Medical Devices: Legal Status in Russia

May 23, 2023

In Russia, only registered medicinal products and medical devices are permitted for circulation. Registration is always accompanied by the issuance of a registration certificate, which contains a specific set of information about the medicinal product or medical device, as well as information about the manufacturer and the holder (owner) of the registration certificate.

In this article, we will examine who the holders (owners) of registration certificates (the "RC") for medicinal products and medical devices are, what rights are granted to them, and what obligations are imposed on them by the legislation of Russia and the countries of the Eurasian Economic Union.

Who Are the Holders (Owners) of an RC for a Medicinal Product?

Part 26.1 of Article 4 of Federal Law No. 61-FZ dated April 12, 2010, On Circulation of Medicinal Products (the "Law on Circulation of Medicinal Products") contains the following definition: "The holder or owner of a registration certificate of a medicinal product is the developer of the medicinal product, the manufacturer of medicinal products, or another legal entity possessing the right of ownership of the registration certificate, which bears responsibility for the quality, efficacy, and safety of the medicinal product."

A similar definition is provided in the Recommendation of the Board of the Eurasian Economic Commission No. 2 dated January 12, 2021, On the Updated Information Guide on Concepts Used within the Eurasian Economic Union in the Sphere of Circulation of Medicinal Products: "marketing authorization holder is a legal entity in whose name a registration certificate [marketing authorization] for a medicinal product has been issued and which bears responsibility for the safety, efficacy, and quality of the medicinal product".

Thus, a possible holder (owner) of an RC for medicines (hereinafter – the "MAH", "RC owner") may be either the developer or manufacturer of the medicinal product itself, or another legal entity in whose name the registration certificate is issued. We also note that despite the use of two terms in the Law on Circulation of Medicinal Products—"holder of the RC" and "owner of the RC"—regulatory acts do not legally distinguish between the functions, rights, and obligations of these persons.

Rights and Obligations of MAHs for Medicinal Products

The rights and obligations of an MAH are scattered throughout the Law on Circulation of Medicinal Products and are also contained in other legal acts. For convenience in reviewing the MAH's functions, we will divide them into obligations related to registration actions and obligations related to the quality control and safety of medicinal products.

1. Obligations related to registration actions and updating rights to the RC.

The obligations of a future MAH begin as early as the stage of preparing an application for the registration of a medicinal product. In accordance with the Rules for Registration and Examination of Medicinal Products for Medical Use, approved by Decision of the Council of the Eurasian Economic Commission No. 78 dated November 03, 2016 (the "Rules for Registration of MPs"), to register a medicinal product, it is necessary to submit an application to the Ministry of Health of Russia and provide an extensive package of documents subject to inclusion in the registration dossier for the medicinal product. The applicant is the future MAH or its representative (a legal entity registered in the territory of Russia or a separate subdivision of a legal entity located in the territory of Russia and authorized by the MAH to perform actions related to the circulation of medicinal products). Since the registration procedure is a complex and lengthy process, clarifications and additions to documents are often required, which also falls upon the MAH.

At the same time, the applicant has the right to choose the EAEU member state where the application for registration of the product will be submitted and, if necessary, the concerned states (states of recognition). They are also granted the right to withdraw their application for registration of the medicinal product at any time before the completion of the procedure.

Furthermore, pursuant to Clause 118 of the Rules for Registration of MPs, the registration authority may impose obligations on the MAH to conduct post-registration studies regarding:

the safety of the medicinal product in case of risks associated with the use of the product;
the efficacy of the medicinal product if the understanding of the disease or clinical methodology indicates that previous efficacy assessments require substantial revision.

The MAH has the right, within 90 working days from the date of receipt of the relevant notification, to submit a written explanation in response to the introduction of such an obligation, based on the results of the review of which the authorized body either removes the post-registration obligations or confirms their validity.

The validity period of a registration certificate for a medicinal product registered for the first time is 5 years. Upon expiration of this period, an indefinite registration certificate for the medicinal product is issued subject to confirmation of its registration (re-registration). To do this, the MAH must submit an application to the authorized body. If the MAH fails to do so before the expiration of the registration certificate, it is recognized as invalid (Clause 124 of the Rules for Registration of MPs).

In addition, after the registration of a medicinal product, a need may arise to make amendments to the registration dossier for the product. According to Clause 143 of the Rules for Registration of MPs, this obligation is also imposed on the MAH. Several other obligations stem from this, namely:

to inform the authorized body of all new information that may require amending the documents and data contained in the registration dossier of the medicinal product;
to notify the authorized body of any ban or restriction on the medical use of the medicinal product imposed in another state and of all other information that may affect the assessment of the benefit-risk balance of the medicinal product;
to ensure the compliance of information about the medicinal product with current scientifically based medical standards, including expert conclusions and recommendations of authorized bodies in the sphere of circulation of medicinal products of other countries.

We also note that the MAH bears the costs of registration, confirmation of registration (re-registration), making amendments to the registration dossier, and examination of medicinal products, as well as other procedures related to registration.

2. Determination of interchangeability of medicinal products.

Since March 2020, due to amendments to the Law on Circulation of Medicinal Products, MAHs have new obligations regarding the establishment of the interchangeability of medicinal products [1]. Thus, in accordance with Part 1.5 of Article 30 of the Law, MAHs of medicinal products recognized as interchangeable are required to submit to the Ministry of Health of Russia applications for making amendments to the registration dossier regarding the information specified in the instruction for medical use of medicinal products. This must be done within 40 working days from the date the Ministry of Health posts information about the necessity of making such amendments. From January 1, 2026, if the MAH does not submit documents for the examination of the medicinal product for interchangeability or does not submit an application for amending the registration dossier, the Ministry of Health will suspend the use of the product.

3. Determination of compliance with Good Pharmaceutical Practices.

State registration of medicines mandatorily requires confirmation of the compliance of the manufacturing site with the rules of Good Manufacturing Practice and obtaining a document confirming this. For this purpose, a pharmaceutical inspection is conducted. The Rules for conducting pharmaceutical inspections were approved by Decision of the Council of the Eurasian Economic Commission No. 83 dated November 03, 2016 (the "EAEU Inspection Rules"). To conduct it, the MAH will need to submit an application and a package of documents provided for by the EAEU Inspection Rules.

4. Compliance with Good Manufacturing Practice.

According to Article 45 of the Law on Circulation of Medicinal Products, the production of medicinal products must comply with the requirements of the rules of good manufacturing practice. Currently, the Rules of Good Manufacturing Practice approved by Order of the Ministry of Industry and Trade of Russia No. 916 dated June 14, 2013 (the "Russian GMP Rules") and the Rules of Good Manufacturing Practice of the EAEU approved by Decision of the Council of the Eurasian Economic Commission No. 77 dated November 03, 2016 (the "EAEU GMP Rules"), which have largely similar norms, are in effect.

The EAEU GMP Rules determine that responsibility for the functioning of the pharmaceutical quality system during production lies with the holder of the authorization (license) for the production of medicinal products and the Qualified Person (QP) authorized by them. There is no mention of the MAH's responsibility in the "General Requirements" section. However, this does not mean that the MAH does not participate in work to ensure the quality of medicinal products. Part of the function of assessing product quality is directly imposed on the MAH. Thus, according to Clause 1.11 of the EAEU GMP Rules, the manufacturer and the MAH (if they are different organizations) must evaluate the results of the product quality review (PQR) and draw conclusions about the need for corrective and preventive actions or re-validation within the pharmaceutical quality system. Procedures for the ongoing management and analysis of such actions must be in place. The effectiveness of these procedures must be confirmed during self-inspection. An agreement must also be concluded between the MAH and the manufacturer establishing the respective obligations of the parties regarding the compilation of the quality review.

Furthermore, as correctly pointed out by some researchers, the most important duties and rights of the MAH concern facilitating compliance with GMP rules by establishing a two-way exchange of information between national regulatory authorities, manufacturing sites, Qualified Persons, and other interested parties. Thus, the manufacturer must inform the MAH of any difficulties in manufacturing operations that may lead to unusual restrictions on supply. Such communication is carried out to simplify the procedure for notifying the authorized bodies of the relevant member states about supply restrictions, sent by the MAH [2]. In cases where a quality defect of the product is identified that may lead to a product recall, the manufacturer must also inform the MAH in a timely manner.

5. Registration and re-registration of prices for medicinal products included in the VED List.

The Law on Circulation of Medicinal Products also establishes certain obligations when determining prices for products. The manufacturer's maximum selling price for medicinal products included in the List of Vital and Essential Drugs (VED List) is subject to state registration [3].

Article 61 of the Law on Circulation of Medicinal Products imposes on the MAH the obligation to submit an application for re-registration of the registered maximum selling price downwards in the following cases:

reduction of the price in foreign currency for the medicinal product in the manufacturer's country or in countries where it is registered or supplied, including for generic, biosimilar medicinal products—reduction of prices for reference medicinal products;
the maximum selling price for the first generic, biosimilar medicinal product of foreign manufacture or from a member state of the Eurasian Economic Union exceeds the manufacturer's maximum selling price for the second generic, biosimilar product calculated in accordance with the methodology approved by the Government of Russia.
obligations related to the quality control and safety of medicinal products.

6. Ensuring pharmacovigilance regarding medicinal products.

Medicinal products in circulation in the Russian Federation are subject to efficacy and safety monitoring in order to identify possible negative consequences of their use (hereinafter – "pharmacovigilance", "PV"). The procedure for carrying out pharmacovigilance is approved by Order of Roszdravnadzor No. 1071 dated February 15, 2017 (the "Order No. 1071"), which is harmonized with the Rules of Good Pharmacovigilance Practice of the EAEU approved by Decision of the Council of the Eurasian Economic Commission No. 87 dated November 03, 2016 (the "GVP Rules").

The GVP Rules determine that MAHs are responsible for performing tasks and obligations regarding PV. To this end, they must ensure the implementation and functioning of their own monitoring of the safety of medicinal products. In particular, the MAH is obliged to:

describe the pharmacovigilance system and maintain it throughout the entire validity period of the registration certificates;
develop a risk management system, a set of actions and measures aimed at identifying, characterizing, preventing, or minimizing risks, and assess the effectiveness of these measures and activities;
ensure proper documentation, handling, and storage of all pharmacovigilance information.

To perform these specified functions, a Qualified Person responsible for Pharmacovigilance (QPPV) possessing the required qualifications must be appointed. The duties of the QPPV must be defined by a job description. The MAH ensures their access to the pharmacovigilance system and grants authority to make changes to the system, risk management plans (RMP), as well as to prepare regulatory actions in response to emergency situations regarding changes in the safety profile.

To confirm the fulfillment of pharmacovigilance obligations, Roszdravnadzor conducts inspections. In accordance with Clause 187 of the GVP Rules, MAHs are obliged to:

always be ready for an inspection, as inspections can be unannounced;
maintain and submit to inspectors, upon request, the Pharmacovigilance System Master File (PSMF) no later than 7 working days after receiving the relevant request;
guarantee obtaining consent for the inspection prior to its commencement from the entities selected for inspection, which may include organizations performing pharmacovigilance functions under an agreement with the MAH;
provide inspectors with any information or documentation necessary for preparing for the inspection within the established timeframes or during the inspection;
guarantee that relevant personnel participating in pharmacovigilance activities or interrelated activities will be present during the inspection and provide clarifications on arising issues;
guarantee the proper and timely implementation of plans for corrective and preventive actions to eliminate deficiencies identified during the inspection, prioritizing critical and major deficiencies.

An important function of the MAH is the work of collecting and reporting to Roszdravnadzor information on adverse reactions arising from the use of medicinal products from various sources. Thus, pursuant to Clauses 394–395 of the GVP Rules, MAHs should:

carry out a systematic review of scientific medical literature in widely used reference databases at least once a week;
verify that the review of scientific medical literature includes viewing databases that contain the maximum number of references to articles relevant to the monitored medicinal product;
ensure that all representative offices of the MAH are aware of publications in local medical journals and inform the safety department of the MAH accordingly;
review reports of suspected adverse reactions published in scientific medical literature, including conference materials or draft monographs, to identify and record such reports as spontaneous reports.

The procedure for reporting identified adverse reactions is regulated in detail in Order No. 1071. Thus, the MAH is obliged to:

report to Roszdravnadzor within a period of no more than 15 calendar days information on identified adverse reactions;
submit Periodic Safety Update Reports (hereinafter – "PSUR"), unless otherwise established by Roszdravnadzor, every 6 months from the date of the first state registration in the world for the first 2 years, annually for the subsequent 2 years, and thereafter every 3 years;
develop, upon Roszdravnadzor's request when non-compliance of the medicinal product with quality, efficacy, and safety requirements is identified, a Risk Management Plan (hereinafter – "RMP") and submit it to Roszdravnadzor within 60 days;
take necessary measures to ensure that the harm associated with the circulation of the medicinal product for which adverse reactions have been revealed does not increase.

Administrative liability is provided for non-submission of information or submission of knowingly false information under Article 19.7.8 of the Code of Administrative Offenses of the Russian Federation (CAO RF). The punishment is an administrative fine for officials in the amount of 10,000 to 15,000 rubles; for legal entities — in the amount of 30,000 to 70,000 rubles. At the same time, according to clarifications given by Roszdravnadzor, liability may be imposed for failure to submit to Roszdravnadzor any information on the safety of medicinal products, including expedited reports, PSURs, and RMPs [4].

Also, Part 1 of Article 237 of the Criminal Code of the Russian Federation provides for criminal liability for concealing or distorting information about events, facts, or phenomena creating a danger to human life or health committed by a person obliged to provide the population and bodies authorized to take measures to eliminate such danger with such information. The maximum punishment is deprivation of liberty for a term of up to 2 years with deprivation of the right to hold certain positions or engage in certain activities for a term of up to 3 years or without such.

We note that the practice of holding liable for violation of the procedure for notifying Roszdravnadzor of adverse reactions is currently sparse, especially regarding MAHs. However, the risk of being held liable always exists. Furthermore, in accordance with Article 32 of the Law on Circulation of Medicinal Products, failure by the MAH to perform measures to ensure the safety of medicinal products provides grounds for the cancellation of the state registration of the medicinal product.

7. Withdrawal of a medicinal product from circulation.

In practice, there are cases of recall from circulation of a specific or all batches of a specific product, which is carried out at the initiative of the manufacturer and brought to the attention of market participants by information letters from Roszdravnadzor. The regulatory acts under consideration do not explicitly disclose the MAH's functions in such a situation. However, in accordance with GMP Rules, the following requirements are established:

Written procedures governing activity regarding the recall of products from sale must be established.
If the manufacturer and the MAH are not the same entity, an agreement must be concluded between them distributing the roles and duties of the manufacturer, the MAH, and third parties regarding assessment, decision-making, dissemination of information, and implementation of actions to reduce the potential danger associated with the defective product.

Rights and Obligations of the Person in Whose Name a Registration Certificate May Be Issued and the Authorized Representative of the Manufacturer of a Medical Device

Federal Law No. 323-FZ dated November 21, 2011, On the Fundamentals of Health Protection of Citizens in the Russian Federation (the "Law on Health Protection") does not contain the term holder (owner) of a registration certificate for a medical device. Moreover, as a general rule, the manufacturer bears responsibility for the circulation of a medical device. However, legislation also uses the terms authorized representative of the manufacturer and person in whose name a registration certificate may be issued.

The Rules for Registration and Examination of Safety, Quality, and Efficiency of Medical Devices, approved by Decision of the Council of the Eurasian Economic Commission No. 46 dated February 12, 2016 (the "Rules No. 46"), provide its definition. Authorized representative of the manufacturer (hereinafter – "ARM") is a legal entity or a physical person registered as an individual entrepreneur, being residents of Russia and authorized by the manufacturer to represent its interests and bear responsibility regarding the circulation of the medical device and the fulfillment of mandatory requirements applicable to medical devices. In accordance with the requirements of Rules No. 46, all foreign manufacturers of medical devices in circulation in the territory of Russia must have an authorized representative. It is their name and location that are entered into the registration certificate together with the name and location of the manufacturer of the medical device.

We note that prior to January 1, 2022, the registration of medical devices was carried out under the rules of national legislation in accordance with Decree of the Government of the Russian Federation No. 1416 dated December 27, 2012. In addition to the authorized representative, this regulatory act also used the term "person in whose name a registration certificate may be issued." Currently, due to the termination of registration under the national procedure, it has lost its relevance.

In many respects, the functions of the ARM are similar to the functions of MAHs for medicinal products. Thus, the manufacturer may impose the following duties on them:

Participation in the implementation of registration actions regarding medical devices. In particular, the ARM, having the appropriate authority from the manufacturer, may act as the applicant during the registration of a medical device, making amendments to the registration dossier, or cancellation (annulment) of the registration certificate.
Interaction with consumers of medical devices regarding their quality, safety, and effectiveness. For example, receiving reports of identified adverse events during their circulation, receiving substandard medical devices from the consumer.
Interaction with Roszdravnadzor regarding control over the circulation of the medical device.

Within the framework of such interaction with the supervisory authority, the ARM carries out:

informing Roszdravnadzor about imported series/batches of medical devices in accordance with Roszdravnadzor Order No. 11020 dated November 25, 2021 [5];
submitting reports on an adverse event during the use of a medical device and reports on field safety corrective actions regarding the medical device, as well as clinical monitoring reports in accordance with Order of the Ministry of Health of Russia No. 1113n dated October 19, 2020 [6].

The initial adverse event report is submitted within the following deadlines:

in the event of a serious threat to health – no later than 2 calendar days after the ARM became aware of the existence of the threat;
in the event of death or unforeseen serious deterioration of the user's health – no later than 10 calendar days after the ARM became aware of the event;
in other cases – no later than 30 calendar days after the ARM became aware of the event.

The ARM has the right to perform corrective actions prior to sending the initial report on corrective actions in emergency cases to protect users or third parties from the threat of death or serious health deterioration. In addition, the ARM has the right to apply to Roszdravnadzor for assistance in accessing the medical device to determine the connection between the use of the medical device and the identified adverse event.

Regarding medical devices of potential risk class 3, as well as those implantable in the human body of potential risk class 2b, the ARM is obliged to conduct monitoring of safety and clinical performance after its registration and annually for 3 years from the moment of its registration. Based on its results, a report on clinical monitoring is submitted to Roszdravnadzor no later than February 1, starting from the year following the year of receipt of the registration certificate.

Summing up, we note that the rights and obligations of MAHs and authorized representatives of manufacturers are contained in a significant number of regulatory acts. At the same time, they do not sufficiently distinguish these from the duties and spheres of responsibility of manufacturers of medicinal products and medical devices. Furthermore, EAEU regulatory regulation often does not contain detailed regulation and requires independent elaboration and approval of operating rules.

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References

[1] Federal Law No. 475-FZ dated December 27, 2019, On Amendments to the Federal Law On Circulation of Medicinal Products and the Federal Law On Amendments to the Federal Law On Circulation of Medicinal Products.

[2] Meshkovsky A.P., Pyatigorskaya N.V., Aladysheva Zh.I., Beregovykh V.V., Pyatigorsky A.M., Nikolenko N.S., Marshalova M.M., Belyaev V.V. Obligations of marketing authorization holders regarding GMP compliance. Drug development & registration // 2020; 9(4):15–20.

[3] Order of the Government of Russia No. 2406-r dated October 12, 2019, On Approval of the List of Vital and Essential Drugs, as well as Lists of Medicinal Products for Medical Use and the Minimum Assortment of Medicinal Products Necessary for Providing Medical Care.

[4] Letter of Roszdravnadzor No. 01i-1420/17 dated June 14, 2017, On New Legislative Requirements for Pharmacovigilance.

[5] Order of Roszdravnadzor No. 11020 dated November 25, 2021, On Approval of the Procedure for Submission by the Manufacturer of a Medical Device (Its Authorized Representative) or a Person Importing Medical Devices into the Territory of the Russian Federation of Information to the Authorized Federal Executive Body Performing Functions of Control and Supervision in the Sphere of Health Protection.

[6] Order of the Ministry of Health of Russia No. 1113n dated October 19, 2020, On Approval of the Procedure for Reporting by Medical Device Circulation Entities of All Cases of Identification of Side Effects Not Specified in the Instructions for Use or Operation Manual of the Medical Device, Adverse Reactions During Its Use, Specifics of Interaction of Medical Devices with Each Other, Facts and Circumstances Creating a Threat to the Life and Health of Citizens and Medical Workers During the Use and Operation of Medical Devices.