Pharmacovigilance in Russia: Legal Regulation

 

March 31, 2023

Anna Ivanova, Associate, BRACE Law Firm ©

Currently, the pharmaceutical market is actively developing, and new medicinal products and developments in the pharmaceutical sphere are appearing. However, on the one hand, this allows for significantly improving the quality of life of patients, improving prognosis, and reducing mortality in many diseases.

On the other hand, the introduction into clinical practice of innovative drugs with high biological activity, the growing sensitization of the population to biologically active and chemical substances, irrational use of medicines, polypharmacy, medical errors, and the presence on the pharmaceutical market of a large number of generics, some of which do not meet quality criteria, have increased the risks of developing adverse reactions during drug therapy. Available data show that adverse reactions are a frequent cause of hospitalization, require additional treatment, and can even lead to patient death [1].

In accordance with the requirements of the World Health Organization (WHO), the tracking and transmission of information on adverse reactions to medicines to the VigiBase database (Uppsala Monitoring Centre) must be carried out only by organized national centers. Each country wishing to become a member of the WHO International Drug Monitoring Programme is required to organize a database and carry out the transmission of information on adverse reactions of medicinal products to the VigiBase database through it. Such databases also exist in all EAEU states ("AIS-Roszdravnadzor" in Russia, "Expertise of Medicinal Products, Medical Devices and Medical Equipment" in Kazakhstan, etc.). At the same time, the issue of PV is also regulated by general EAEU legal acts applicable to all member states [2].

In this regard, measures regarding the monitoring of drug efficacy (pharmacovigilance) are consolidated at the legislative level.

From January 1, 2017, the Rules of Good Pharmacovigilance Practice (GVP) of the Eurasian Economic Union, approved by Decision of the Council of the Eurasian Economic Commission No. 87 dated November 3, 2016 (hereinafter, "EAEU GVP"), entered into force. The Agreement of the EAEU countries on common principles for the circulation of medicinal products states that national pharmacovigilance systems are brought into compliance with GVP (Good Pharmacovigilance Practices).

No transition period is provided for. In this regard, Roszdravnadzor approved the Procedure for Pharmacovigilance, approved by Order No. 1071 dated February 15, 2017 (hereinafter, the "Procedure for Pharmacovigilance"), harmonized with the EAEU Good Pharmacovigilance Practice and Good Clinical Practice rules.

According to Part 52.1 of Article 4 of Federal Law No. 61-FZ dated April 12, 2010, "On the Circulation of Medicinal Products" (hereinafter, the "Law on Circulation of Medicinal Products", "Law No. 61-FZ"), pharmacovigilance (PV) is a type of activity for monitoring the efficacy and safety of medicinal products, aimed at identifying, assessing, and preventing adverse consequences of the use of medicinal products.

In accordance with the Procedure for Pharmacovigilance, PV is carried out by the Federal Service for Surveillance in Healthcare (Roszdravnadzor) by analyzing information submitted by entities involved in the circulation of medicinal products regarding side effects of medicinal products, adverse reactions, serious adverse reactions, unexpected adverse reactions during the use of medicines, individual intolerance, lack of efficacy of medicinal products, as well as other facts and circumstances posing a threat to the life or health of a human when using medicines, identified at all stages of their circulation in Russia and other states in order to identify possible negative consequences of their use, individual intolerance, and to warn medical workers, patients, and protect them from the use of such medicines [3].

According to Article 65 of Law No. 61-FZ, holders or owners of registration certificates (Marketing Authorizations) for medicinal products, and legal entities in whose name permits for conducting clinical trials in Russia are issued, are required to receive, record, process, analyze, and store reports received by them from entities involved in the circulation of medicinal products and state authorities regarding side effects, adverse reactions, serious adverse and unexpected adverse reactions during the use of medicines, peculiarities of their interaction with other medicines, individual intolerance, as well as other facts and circumstances posing a threat to the life or health of a human or influencing a change in the benefit-risk balance of using medicinal products.

Upon identification of the indicated facts, it is necessary to take measures aimed at eliminating the negative consequences of the use of such medicinal products, preventing harm to the life or health of a human, protecting them from the use of such medicines, and collecting additional data on their efficacy and safety.

If Roszdravnadzor, within the framework of its pharmacovigilance activities, receives evidence of the non-compliance of medicines with established requirements or receives information on the non-compliance of data on the efficacy and safety of a medicinal product with the data contained in its instructions for use, Roszdravnadzor considers the issue of suspending the use of such a medicine.

In this article, we examine in more detail the main issues of the legal regulation of pharmacovigilance.

EAEU Good PV Practice Rules

According to Clause 3 of Article 30 of the Treaty on the Eurasian Economic Union (Signed in Astana on May 29, 2014), one of the main principles of forming a single market within the EAEU is the adoption of unified rules in the sphere of circulation of medicinal products. Based on the specified legal norm, the Good Pharmacovigilance Practice Rules of the Eurasian Economic Union (EAEU GVP) were developed.

It is noteworthy that the Russian Federation lacks developed rules for good pharmacovigilance practice; that is, the specified EAEU document is the primary one for Russia, and no transitional provisions directed at the gradual implementation of EAEU GVP into Russian legislation have been established. In this regard, EAEU GVP is mandatory for application in Russia from the date of its approval. Let us consider the main provisions contained in EAEU GVP.

According to Clause 2 of this legal act, pharmacovigilance is a type of scientific and practical activity aimed at identifying, assessing, understanding, and preventing adverse consequences of the use of medicinal products. Pharmacovigilance represents an activity aimed at protecting the health of patients and the population.

PV Quality System

An integral part of pharmacovigilance is the quality system, which must include: proper resource management, compliance control with the requirements of EAEU acts and the legislation of member states, and documentation management.

All specialists performing work on the organization of the quality system are responsible for ensuring the operation of the pharmacovigilance system in accordance with quality system requirements. It is necessary to ensure a sufficient number of competent and trained specialists to perform the required volume of pharmacovigilance work.

To do this, the organization must develop a training plan for PV specialists, which must be based on an assessment of training needs. The development and execution of the plan are subject to control and monitoring. Training must include initial training and subsequent training throughout the entire period of work in accordance with the functions performed and tasks assigned.

In addition to personnel training requirements, achieving the required level of quality in the implementation of pharmacovigilance processes and results obtained is also associated with providing the system with the necessary facilities and equipment used in these processes.

Facilities and equipment must be located, designed, adapted, and maintained in such a way as to correspond to the set goal according to quality objectives in pharmacovigilance. Facilities, equipment, and their functional properties important for the implementation of pharmacovigilance are subject to appropriate verification. To determine the scope of verification, qualification, or validation, a documented risk assessment should be used. This risk management method must be applied throughout the entire service life of facilities and equipment.

Documentation Management System in PV

Also, an integral part of the proper implementation of pharmacovigilance is documentation maintenance. The documentation management system ensures data retrievability and traceability of performed procedures, including procedures for assessing new data and investigating safety-related problems concerning the correctness of process execution, investigation timeframes, and decision-making.

The documentation management system must ensure:

• Quality management of pharmacovigilance data, including their completeness, accuracy, and integrity;
• Access to all records;
• Effective internal and external data transfer;
• Retention of documents related to pharmacovigilance systems and the implementation of pharmacovigilance for each medicinal product, according to applicable retention periods.

In addition to the specified requirements, the Marketing Authorization Holder (MAH) must ensure proper documentation, handling, and storage of all pharmacovigilance information for the purpose of executing procedures for accurate reporting, interpretation, and verification of data.

The documentation management system must provide for special measures at each stage of data storage, processing, and transfer.

All elements, requirements, and provisions of the quality system must be documented and systematized appropriately in the form of:

• A quality plan;
• A quality manual;
• Quality procedures and quality reports.

The quality plan determines the main objectives of the quality system and the processes that must be implemented to achieve the set objectives. Quality procedures represent a description of the established order of process execution and may take the form of standard operating procedures (SOPs) and work instructions or guides. The quality manual determines the scope of the quality system, quality system processes, and their interrelation. Quality reports include the results of system operation or confirmation of activities performed.

Quality system documentation must also include:

• Methods for monitoring the effectiveness of the quality system and, in particular, its ability to achieve quality objectives;
• Documentation management policy;
• Documents on the results of executed pharmacovigilance procedures confirming the completion of prescribed stages and actions;
• Documents and reports on facilities and equipment, including verification of functional properties, qualification, and validation activities, which confirm the completion of all stages provided for by relevant requirements, protocols, and procedures;
• Documents confirming the control of deficiencies and deviations from the established quality system, the adoption of preventive and corrective actions (CAPA), and the assessment of the effectiveness of measures taken.

In addition to the required quality system documentation, the authorized body must document the organizational structure, distribution of tasks and responsibilities among all pharmacovigilance system personnel, and define contact persons to ensure interaction between authorized bodies, Marketing Authorization Holders, and persons presenting information on risks of medicinal products regarding their impact on patient health and public health (population health).

In general, the effectiveness of the quality system functioning must be regularly assessed by a manager performing a review of quality system documentation, the frequency and intensity of which are determined by preliminary planning, justified risk, and developed system review programs.

Marketing Authorization Holders

Marketing Authorization Holders (MAHs) are responsible for performing pharmacovigilance tasks and duties. To this end, they must ensure the functioning of the pharmacovigilance system in the territories of member states, including the implementation of an appropriate and effective quality system for the pharmacovigilance system.

Under certain circumstances, MAHs are permitted to organize more than one pharmacovigilance system, for example, in the case of forming a separate pharmacovigilance system for certain groups of medicinal products (in particular for vaccines, over-the-counter medicines).

It is important to note that the MAH has the right to delegate all or part of its pharmacovigilance tasks (including the functions of the Qualified Person responsible for pharmacovigilance) to another organization or person. At the same time, the MAH bears responsibility for the performance of pharmacovigilance tasks and duties, quality assurance, and the integrity of the PV system.

In the case of delegating certain pharmacovigilance tasks to another organization, the MAH is responsible for applying an effective quality system for the execution of these tasks. Requirements for the PV system defined by Good Pharmacovigilance Practice also apply to this organization.

When delegating tasks to another organization, the MAH ensures detailed, clear, and constantly updated documentation of contractual arrangements between it and the other organization, describing the arrangements for delegated tasks.

PV Inspections

To confirm the fulfillment of pharmacovigilance obligations by Marketing Authorization Holders, Roszdravnadzor conducts inspections.

The objectives of pharmacovigilance inspections are:

• Confirming that the MAH has the personnel, systems, as well as premises, facilities, and equipment necessary to fulfill pharmacovigilance obligations;
• Identifying, assessing, and recording non-compliances that may pose a danger to public health, and informing the inspected party thereof;
• Using inspection results as a basis for mandatory actions for the MAH (if necessary).

Inspections can be routine (planned) and "for cause" (unscheduled), pre-authorization and post-authorization, announced and unannounced. Let us consider these classifications in more detail.

Routine (planned) inspections of the PV system are conducted in accordance with a pre-compiled inspection plan and represent system inspections, while allowing for the possibility of choosing one or several specific medicinal products as examples for verification.

"For cause" (unscheduled) inspections are conducted in the event of an initiating factor (systemic problem) being identified and are aimed at assessing specific pharmacovigilance processes or include the study of an identified problem (issues) and its impact on a specific medicinal product.

Pre-authorization inspections are performed before the issuance of a registration certificate (Marketing Authorization) to the applicant with the aim of studying the functioning or planned pharmacovigilance system in accordance with the system description submitted by the applicant. Such inspections are not mandatory, but their conduct may be necessary.

Post-authorization pharmacovigilance inspections are conducted after the issuance of the registration certificate and are intended to assess the fulfillment by the MAH of its pharmacovigilance obligations.

Most pharmacovigilance system inspections are announced, which implies notifying the inspected party of the need to ensure the presence of relevant persons at the inspection site during the inspection. In a number of cases, it is appropriate to conduct unannounced inspections or notify the inspected party on the eve of the inspection (for example, if a preliminary announcement may jeopardize the inspection objectives or if the inspection is conducted urgently within a short timeframe for reasons related to safety threats).

Also, EAEU GVP enshrines the right to conduct remote inspections. These are conducted by inspectors without traveling to the Marketing Authorization Holder.

Marketing Authorization Holders are required to:

• Always be ready for an inspection, as inspections may be unannounced;
• Maintain and submit to inspectors upon request, no later than 7 working days after receiving the relevant request, the Pharmacovigilance System Master File (PSMF);
• Guarantee obtaining consent prior to the inspection for conducting the inspection from entities selected for inspection, which may include organizations performing pharmacovigilance functions under an agreement with the MAH;
• Provide inspectors with any information and (or) documentation necessary for inspection preparation within established deadlines or during the inspection;
• Guarantee that relevant personnel participating in pharmacovigilance activities or related 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 (CAPA) to eliminate deficiencies (non-compliances) identified during the inspection, establishing priorities for critical and major deficiencies (non-compliances).

Risk Management System

The risk management process consists of the following interrelated and repeating stages:

• Compiling a safety profile characterization of the medicinal product defining important identified and potential risks and missing information;
• Planning PV activities for risk characterization and identification of new risks, as well as increasing the general level of knowledge about the safety profile of drugs (pharmacovigilance plan);
• Planning and implementing activities for risk minimization.

The risk management system must be proportionate to the identified and potential risks of using the medicinal product, as well as the need to obtain safety data at the post-authorization stage.

The Risk Management Plan (RMP) must focus on those risks that are relevant to risk management activities associated with the use of the registered medicinal product.

In the RMP, the main attention should be directed to important identified risks that may influence the benefit-risk balance of the medicinal product.

Identified risks include:

• Adverse reactions reliably demonstrated in preclinical studies and confirmed by clinical trial data;
• Adverse reactions included in the Summary of Product Characteristics (SmPC), except for cases where they are effects specific to the pharmacological class and indicated in the general characteristics but not described directly for the given drug (in this case, such a risk is a potential risk).

Regarding an important identified risk that must be included in the RMP, it is generally necessary to:

• Perform further risk assessment within the framework of the pharmacovigilance plan;
• Implement risk minimization activities: including recommendations in the medicinal product information regarding specific clinical measures that must be taken to minimize the risk.

Important potential risks that must be included in the RMP are risks that, upon subsequent characterization and confirmation, may influence the benefit-risk balance of the medicinal product.

Examples of potential risks include:

• Risks established by results of preclinical toxicological studies that were not observed or were rejected by results of clinical trials;
• Adverse events observed in clinical or epidemiological studies in which the degree of difference in the parameter characterizing the risk compared to the control group suggests a causal relationship but is insufficient to confirm a causal relationship;
• A signal received from the spontaneous adverse reaction reporting system;
• A risk for which an association with other active substances within the same class is known or the development of which is assumed based on the properties of the medicinal product.

Thus, the Risk Management Plan is a dynamically changing document that must be updated throughout the entire lifecycle of the medicinal product.

Adverse Reactions

Roszdravnadzor and Marketing Authorization Holders should collect and organize reports of suspected adverse reactions received from various sources without a preliminary request (unsolicited) and received upon request (solicited).

The pharmacovigilance system must be designed in such a way as to ensure proper quality assessment of collected adverse reaction reports.

Safety information reports collected at the post-authorization use stage can be divided into two types: unsolicited reports and solicited reports.

A spontaneous report is sent by a healthcare professional, patient, or consumer to Roszdravnadzor, the MAH, or another organization (e.g., a regional pharmacovigilance center, poison control center) without a preliminary request. A spontaneous report describes one or more suspected adverse reactions in a patient who was administered the medicinal product.

In the event of receiving a spontaneous report of an adverse event development in which there is no indication of a causal relationship, this adverse event is considered an adverse reaction.

Thus, all incoming spontaneous reports submitted by healthcare professionals, patients, or consumers are considered suspected adverse reactions based on the fact that their submission contains an assumption by the primary source of the report about the existence of a relationship between the adverse event and the intake of the suspected medicinal product.

Furthermore, scientific medical literature is an important source of information for monitoring the safety profile and the benefit-risk balance of medicinal products.

Marketing Authorization Holders should carry out a systematic review of scientific medical literature in widely used reference databases no less than once a week.

If the MAH becomes aware of a report of a suspected adverse reaction from a non-medical source, for example, from non-specialized print publications or other media, it should process this report in accordance with approaches recommended for spontaneous reports.

It is also necessary to regularly monitor the Internet and digital media for potential reports of suspected adverse reactions.

Reports of suspected adverse reactions received upon request (solicited reports) come from organized data collection systems, which include clinical trials, non-interventional studies, registries, personalized programs for the use of unregistered medicines, and disease monitoring, patient or medical worker surveys, or collection of data on medicinal product efficacy or patient adherence.

If the initial report contains incomplete information about suspected adverse reactions, follow-up work should be conducted to obtain additional detailed information.

Reports of suspected adverse reactions should be stored on paper media, in the form of electronic documents, and handled in the same manner as other medical records.

To ensure the safety and confidentiality of pharmacovigilance data, strict control of access to documents and databases should be ensured, and access rights should be granted only to authorized pharmacovigilance system personnel.

Personnel must be instructed on the data entry procedure using special terminology, and personnel qualifications must be periodically confirmed.

When storing data electronically, traceability of all entered or modified data must be ensured, including information on dates and sources of received data, as well as dates and places to which this data is transferred.

We have examined the main requirements for the implementation of pharmacovigilance. In fact, EAEU GVP contains substantive norms and partially touches upon procedural issues of pharmacovigilance implementation. However, member states of the EAEU have developed procedures for pharmacovigilance implementation regulating the process in more detail. Let us examine the corresponding procedure operating in Russia in more detail.

Procedure for Pharmacovigilance Implementation in Russia

Pharmacovigilance is carried out by Roszdravnadzor by analyzing information submitted by entities involved in the circulation of medicinal products regarding side effects of medicinal products, adverse reactions, serious adverse reactions, unexpected adverse reactions during the use of medicinal products, individual intolerance, lack of efficacy (adverse reactions), as well as other facts and circumstances posing a threat to the life or health of a human when using medicines. Such facts can be identified at all stages of drug circulation.

PV is carried out by Roszdravnadzor based on information received in the form of:

• Reports from entities involved in the circulation of medicinal products;
• Periodic Safety Update Reports (hereinafter, "PSURs") sent to Roszdravnadzor by holders or owners of registration certificates for medicinal products or other legal entities authorized by them;
• Development Safety Update Reports (hereinafter, "DSURs") sent to Roszdravnadzor by legal entities in whose name permits for conducting clinical trials in the Russian Federation are issued, or other authorized legal entities;
• Information obtained during the implementation of state control (supervision) in the sphere of circulation of medicinal products.

For the purpose of assessing scientific and clinical information indicated in the data listed above, Roszdravnadzor engages a Federal State Budgetary Institution under the jurisdiction of Roszdravnadzor.

Forms of reports from entities involved in the circulation of medicinal products to Roszdravnadzor are given in Appendices No. 1 and 2 to the Procedure for Pharmacovigilance. At the same time, if the nature of the information does not correspond to the content of the specified report forms, its submission to Roszdravnadzor in free form is allowed.

Reports are sent to Roszdravnadzor via the Automated Information System of Roszdravnadzor (hereinafter, "AIS Roszdravnadzor"), or by email. PSURs and DSURs are submitted only via AIS Roszdravnadzor.

Holders of registration certificates for medicinal products are assigned the obligation to report information on adverse reactions to Roszdravnadzor within a period of no more than 15 calendar days.

For medicinal products for which the terms and frequency of PSUR submission have not been approved by Roszdravnadzor, the frequency and deadlines for PSUR submission are counted from the date of the first state registration of the medicinal product in the world and constitute:

• Every 6 months from the date of the first state registration in the world during the first 2 years;
• Annually during the subsequent 2 years;
• Thereafter – every 3 years.

Upon identification of adverse reactions and other safety and efficacy information not contained in the instructions for medical use that change the ratio of expected benefit to possible risk of using the medicinal product, Roszdravnadzor has the right to request an ad hoc (unscheduled) PSUR.

DSURs are submitted to Roszdravnadzor annually within a period calculated from the date of the start of the first clinical trial of the medicinal product in the world or from the date of its first state registration in the world.

DSURs for medicinal products being investigated in the territory of Russia are submitted to Roszdravnadzor within a period not exceeding 60 calendar days from the data lock point (date of completion of collection) by the MAH of information on adverse reactions for the given medicinal product.

Entities involved in the circulation of medicinal products (medical organizations) are required to report to Roszdravnadzor within no more than 3 working days about serious adverse reactions with a fatal outcome or threat to life, with the exception of adverse reactions identified during clinical trials conducted in the given medical organization.

Entities involved in the circulation of medicinal products (medical organizations) report to Roszdravnadzor within a period not exceeding 15 calendar days about the following adverse reactions and other safety and efficacy information identified by the given medical organization, with the exception of adverse reactions identified during clinical trials:

• Serious adverse reactions to medicinal products, excluding serious adverse reactions (reactions with a fatal outcome or threat to life, excluding adverse reactions identified during clinical trials conducted in the given medical organization);
• Cases of transmission of an infectious disease via a medicinal product;
• Cases of lack of claimed efficacy of medicinal products used for diseases posing a threat to human life, vaccines for the prevention of infectious diseases, medicines for preventing pregnancy, when the lack of clinical effect is not caused by individual characteristics of the patient and (or) the specifics of their disease;
• Adverse reactions arising from drug abuse, in cases of intentional overdose, during exposure related to professional activity, or in cases of use for the purpose of intentionally causing harm to human life and health.

Cases of individual intolerance to medicinal products, which served as grounds for prescribing medicinal products by trade name within the framework of preferential drug provision programs, are subject to submission to Roszdravnadzor by medical commissions within a period no later than 5 working days from the date of prescribing the corresponding medicinal product by trade name.

The period for reporting adverse reactions and other safety and efficacy information is calculated from the date when the official responsible for pharmacovigilance of the entity involved in the circulation of medicinal products (medical organization) became aware of the following information about the adverse reaction or special situation:

• Information allowing identification of the legal entity or individual who identified the adverse reaction or special situation;
• Information allowing identification of the individual in whom the adverse reaction was observed;
• Information allowing identification of the medicinal product;
• Information allowing identification of the symptoms of the adverse reaction.

Reports received by Roszdravnadzor by email, as well as PSURs and DSURs received by Roszdravnadzor on electronic media, are registered and entered into AIS Roszdravnadzor within 5 working days from the date of their receipt.

Assessment of scientific and clinical information contained in reports entering AIS Roszdravnadzor is carried out by the expert organization within 5 working days from the date of receipt.

Assessment of scientific and clinical information contained in PSURs and DSURs is carried out by the expert organization within 60 working days from the date of their receipt by the expert organization.

Results of the assessment of scientific and clinical information contained in reports are sent to Roszdravnadzor by the expert organization as part of weekly reports.

Results of scientific and clinical information contained in PSURs and DSURs are sent to Roszdravnadzor as part of monthly reports of the expert organization.

If, according to the conclusion of the expert organization, the cause of the adverse reaction or threat to human life and health could be a violation by entities involved in the circulation of medicinal products of legislative requirements for pharmacovigilance, or violation of good clinical practice rules, Roszdravnadzor makes a decision to conduct an inspection of compliance by entities involved in the circulation of medicinal products with requirements established by the Law on Circulation of Medicinal Products for clinical trials of medicines, storage, transportation, import into Russia, dispensing, sale of medicinal products, and use of medicinal products.

If, according to the conclusion of the expert organization, the cause of the adverse reaction could be the non-compliance of the medicinal product with quality requirements, Roszdravnadzor makes a decision to conduct selective quality control of the corresponding medicinal product in the manner established by the legislation of the Russian Federation.

Within 5 working days from the date of receipt of the expert organization's conclusion containing information on the identification of new safety and efficacy data for medicines not contained in the instructions or clinical trial documentation, changing the ratio of expected benefit to possible risk of using medicinal products, Roszdravnadzor notifies the Marketing Authorization Holder about this via AIS Roszdravnadzor or by posting an information letter on its official website.

The Marketing Authorization Holder conducts a verification of the reliability of the received information within 10 working days from the moment of receiving the notification and submits information on the verification results to Roszdravnadzor.

During the verification period, necessary measures are taken to ensure that harm associated with the circulation of the corresponding medicinal product does not increase.

Within 10 working days from the date of receipt of verification results or results of selective quality control of the medicinal product, Roszdravnadzor notifies the Ministry of Health of Russia about the identification of new safety and efficacy data for medicinal products not contained in the instructions for medical use or clinical trial documentation and sends relevant information for consideration of the issue of the necessity of amending the registration dossier of the medicinal product, cancellation of state registration, conducting preclinical or clinical trials, or other additional quality, efficacy, and safety studies, as well as the necessity or absence of necessity to suspend the circulation of the medicinal product for the period of conducting additional studies or the period of introducing amendments to the registration documentation.

Based on the results of reviewing the verification results, Roszdravnadzor has the right, within 30 working days from the date of their receipt, to send the Marketing Authorization Holder a request for the necessity of developing a Risk Management Plan (hereinafter, "RMP"). The submission of the RMP is carried out within 60 working days from the date of receipt of the request from Roszdravnadzor. The MAH also has the right to develop an RMP independently.

Within 5 working days from the date of receipt of the RMP, Roszdravnadzor sends it to the expert organization for conducting a scientific-clinical assessment to determine the sufficiency of the proposed measures.

The conclusion of the expert organization on the sufficiency of measures proposed by the RMP is sent to Roszdravnadzor within 20 working days from the date of receipt of the RMP.

Within 5 working days from the date of receipt of the expert organization's conclusion, Roszdravnadzor sends the Marketing Authorization Holder of the medicinal product a notification of approval of the RMP or a notification of the necessity to amend the RMP.

Changes to the RMP (if necessary) are made by the Marketing Authorization Holder within a period not exceeding 20 working days from the day of receiving the corresponding notification.

Based on PV results, Roszdravnadzor posts on its official website information about:

• Identification of new confirmed data on side effects, adverse reactions, serious adverse reactions, unexpected adverse reactions during the use of a medicinal product, including those influencing the ratio of expected benefit to possible risk of using the given medicinal product;
• Decisions taken by the Ministry of Health of Russia on amending the instructions for use of the medicinal product, on suspending the use or withdrawing the medicinal product from circulation, or on resuming its use.

In addition to the specified Procedure for Pharmacovigilance, Roszdravnadzor, together with the Ministry of Health, provides clarifications regarding pharmacovigilance work in medical organizations. Namely, it is clarified that patients who have independently identified adverse reactions have the right to demand that the attending physician or other medical worker fill out this notification and send it to Roszdravnadzor. In these cases, in the absence of symptoms of an adverse reaction at the time of the patient's appeal, it is permissible to indicate that the adverse reaction report was filled out based on the patient's words. It is noted that filing a notification via AIS Roszdravnadzor is most preferable [4].

The "Pharmacovigilance" database of AIS Roszdravnadzor began operation on April 1, 2019. It accepts notifications of adverse reactions or lack of therapeutic effect of medicinal products, reports of serious unexpected adverse reactions studied in a clinical trial, periodic safety update reports for medicinal products, and development safety update reports for developed (investigational) medicines [5]. Roszdravnadzor has posted detailed step-by-step instructions for starting work in the specified database on its official website. The procedure for registration/reregistration of users of the "Pharmacovigilance" resource is described in the subsection "Automated system 'Pharmacovigilance'" of the "Services" section of the official Roszdravnadzor website [6].

Practical Issues of Pharmacovigilance Implementation

A borderline issue related to the implementation of pharmacovigilance is the prescription of medicinal products not in accordance with the instructions ("off-label"). Thus, EAEU GVP provides a definition for the concept of "off-label use". This is the intentional use of a medicinal product for a medical purpose not in accordance with the summary of product characteristics or instructions for medical use. On the one hand, current Russian legislation approves a single condition for the use of a medicinal product – compliance with the instructions for medical use.

On the other hand, there are clinical guidelines in which some medicinal products are indicated for treating patients according to off-label indications.

For example, the Temporary Methodological Recommendations "Prevention, Diagnosis and Treatment of New Coronavirus Infection (COVID-19). Version 11 (07.05.2021)", approved by the Ministry of Health of Russia, provide a list of medicinal products for pathogenetic therapy outside the instructions for medical use: Tocilizumab, Baricitinib, Sarilumab, Canakinumab, Olokizumab, and others.

Thus, it follows from the above acts that, despite definitions formulated at the federal legislation level, the actual off-label use of medicinal products takes place in clinical practice. Most often, off-label prescriptions occur in the following groups of patients: children, pregnant women, patients with orphan, oncological, mental diseases, elderly and senile patients. Patients with the new coronavirus infection must also be added to this list [7]. At the same time, it must not be forgotten that patients who have been prescribed off-label drugs are in a risk group regarding the identification of possible adverse reactions. In this regard, it is important to timely inform them, as well as the attending physician, about the procedure for transferring information to Roszdravnadzor about corresponding side effects and other adverse reactions caused by the use of the medicinal product.

Thus, in accordance with clauses 497–498 of EAEU GVP, the use of a medicinal product not in accordance with the summary of product characteristics or instructions for medical use may be conditioned by various reasons. Examples include cases of drug use with intentional non-compliance with conditions, such as:

• Use of a medicinal product not in accordance with approved indications for use;
• Use in a group of patients for whom the use of the medicinal product is not recommended;
• Difference in the route of administration or method of administration;
• Difference in dosing regimen.

The necessity of submitting reports on cases of using a medicinal product not in accordance with the summary of product characteristics or instructions for medical use is determined based on the following conditions according to the result of use regarding causing harm to the health or life of the patient:

• Use not in accordance with the summary of product characteristics or instructions for medical use with harm caused to the patient as a result of the development of a suspected adverse reaction;
• Use not in accordance with the summary of product characteristics or instructions for medical use without harm caused to the patient and a suspected adverse reaction.

Legal Liability for Violation of Pharmacovigilance Rules

At the same time, current legislation provides for liability for failure to submit or untimely submission of information to Roszdravnadzor if the submission of such information is mandatory in accordance with healthcare legislation. Including in the case of failure to submit information on adverse reactions within the framework of pharmacovigilance.

According to Article 19.7.8 of the Code of Administrative Offenses of the Russian Federation, such failure to submit entails the imposition of an administrative fine on officials in the amount of 10,000 to 15,000 rubles; on legal entities – in the amount of 30,000 to 70,000 rubles.

Also, for violation of the procedure for pharmacovigilance, responsible persons of a pharmaceutical organization may be held administratively liable in the form of a remark, reprimand, or dismissal (Article 192 of the Labor Code of the Russian Federation).

Furthermore, 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 said information. Such an act is punishable by a fine in the amount of up to 300,000 rubles or in the amount of the wage or other income of the convicted person for a period of up to 2 years, or forced labor 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, or imprisonment 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.

At the same time, the practice of prosecution for criminal liability for violation of the procedure for notifying Roszdravnadzor about adverse reactions in the order of pharmacovigilance implementation is currently sparse.

Based on the foregoing, it can be concluded that pharmacovigilance represents one of the systemic aspects of ensuring the safety of the circulation of medicinal products, aimed at improving product quality and obtaining new information that was not possible to investigate before the state registration of the medicinal product and its introduction into civil circulation in the territory of the Russian Federation. In this regard, the final procedure is the suspension of the use of a medicinal product in cases where information obtained within the framework of pharmacovigilance indicates a possible threat to human life or health, as well as non-compliance of data on efficacy and safety of medicines.

It follows from this that problems of improper use of medicinal products and harm that a person can cause to themselves (adjusted for the difference in forms of guilt) should be considered as insufficient awareness. This fact relates to the problems of the development of the healthcare system regarding the formation of a responsible attitude of citizens towards their health.

Thus, the analysis of legal sources and scientific literature allowed us to conclude that through ensuring the safety of the circulation of medicinal products, the principle of health protection is realized, where safety implies a guarantee that the state excludes the circulation of medicinal products that do not meet established requirements, and in case of detection, undertakes an obligation to react [8].

This article has examined the main features of the legal regulation of pharmacovigilance in Russia. At the same time, one cannot ignore the fact that the institute of pharmacovigilance in Russia is currently developing, and issues related to the application of EAEU GVP are actually resolved through the formation of law enforcement practice, as well as obtaining relevant clarifications from Roszdravnadzor and ensuring work transparency thanks to AIS "Roszdravnadzor" with the introduction of the "Pharmacovigilance" database.

________________________

References

[1] Role and practice of pharmacovigilance in Russian healthcare. M.A. Murashko, D.V. Parkhomenko, I.L. Asetskaya, V.V. Kosenko, V.A. Polivanov, S.V. Glagolev. 01.10.2014. Remedium.

[2] Actual changes in the pharmacovigilance system in Russia and the EAEU. G.N. Gildeeva, A.V. Belostotsky // Pharmacoeconomics. Modern Pharmacoeconomics and Pharmacoepidemiology. 2019. Vol. 12. No. 2.

[3] Pharmacovigilance system in Russia and the EAEU. S. Simeniv, O. Latysheva, D. Kryuchkov, P. Fedorov, T. Syrova. 27.12.2017.

[4] Letter of the Ministry of Health of the Russian Federation dated 17.02.2020 No. 02I-313/20 "On the organization of pharmacovigilance work in medical organizations".

[5] Letter of Roszdravnadzor dated 29.03.2019 No. 01i-841/19.

[6] Letter of Roszdravnadzor dated 08.04.2019 No. 01i-945/19.

[7] Medico-legal aspects of prescribing medicinal products off-label. Yu.D. Sergeev, Yu.V. Bisyuk, V.A. Verikovsky, I.V. Goleva, G.N. Chernikova // Medical Law. 2021. No. 4. P. 7.

[8] Shevyrev D.N. Safety of circulation of medicinal products: essence and content // Administrative Law and Procedure. 2020. No. 2. P. 78.