Pharmacovigilance check of certified medicines. What is pharmacovigilance, regulations, regulatory measures

Pharmacovigilance is a special type of government measures that allow assessing the safety and effectiveness of drugs used in medical practice. The main recommendations for organizing pharmacovigilance in a medical institution are given. Checklist and useful information for downloading

Pharmacovigilance is a special type of government measures that allow assessing the safety and effectiveness of drugs used in medical practice.

This type of state control is regulated by Roszdravnadzor Order N 1071: on the procedure for implementing pharmacovigilance

On April 1, 2019, a new national database of information on side effects of drugs began operating at external.roszdravnadzor.ru. The full transition to it occurred on September 1.

The database automatically processes messages sent using software from Russian medical institutions, as well as:

the results of international drug safety monitoring conducted by WHO are stored;
offers users modern methods for analyzing security data;
Russian translation of MedDra regulatory information is supported.

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From the article you will learn

Why and by whom is pharmacovigilance carried out?

– one of the areas of government activity, the objectives of which are:

Constantly monitoring the safety and effectiveness of medications.
Identification and prevention of negative reactions when using medications.

Pharmacovigilance of a drug allows you to warn health workers and patients and protect them from the use of low-quality and ineffective drugs in medical practice.

The organization of the pharmacovigilance system in Russia for the use of drugs is stated in the order of Roszdravnadzor No. 1071 dated February 15, 2017, it provides the procedure for organizing control measures in this area.

Pharmacovigilance is carried out by Roszdravnadzor of the Russian Federation; it is this agency that implements the main goals of pharmacovigilance and analyzes information received from all subjects of medicine circulation (for example, from medical institutions, holders of registration certificates, etc.).

Subjects submit the following information to the department for further analysis:

about the presence of undesirable reactions during the direct use of medications (including unexpected and serious ones;
about the presence of side effects when using medications;
about cases of individual intolerance to medications by patients;
about the ineffectiveness of specific drugs;
about other circumstances that indicate the presence of a threat to patients when using a particular drug.

Last changes

Requirements for internal quality control have become uniform. An algorithm that will help quickly restructure work according to new requirements is in the magazine “Deputy Chief Physician”.

Regulations

The pharmacovigilance system in Russia is ensured by the following basic regulatory sources:

Basic Law – “On the Circulation of Medicines.
Pharmacovigilance procedure approved by Roszdravnadzor Order No. 1071.
Selective control of medications - order of the Ministry of Health of the Russian Federation No. 5539 dated September 7, 2015.
European pharmacovigilance standards GVP, approved in 2016 by the Council of the Eurasian Economic Commission.
Uniform rules and principles for the circulation of medical products in force within the EEC countries.

Pharmacovigilance in the drug circulation system

In the process of circulation of medicines for the implementation of the pharmacovigilance system, entities send notifications to Roszdravnadzor in approved forms.

These include the following forms:

notification of an adverse reaction or lack of therapeutic effect of a medicinal product;
reports of a serious unexpected adverse reaction to a drug being studied in a clinical trial.

Any subject who has doubts about the safety of medicines, as well as if adverse reactions and other manifestations are identified, can send an email to Roszdravnadzor or send a message through the department’s unified information system.

Pharmacovigilance in a specific medical institution is organized with the aim of identifying signs of unsafe use of drugs for medical use and is regulated by a set of local acts approved by the chief physician.

note

Roszdravnadzor has begun to more often hold medical organizations accountable for violations in the provision of ambulance and emergency care. The department's expert explained how to reduce risks and prepare for emergency situations. The magazine “Deputy Chief Physician” contains ready-made styling and instructions for staff.

In particular, an authorized person for pharmacovigilance is appointed in a medical institution. It is the agency that sends reports to the department about the unsafety or ineffectiveness of medications.

When to inform regulatory authorities about adverse drug reactions

The table below shows the time frame within which Roszdravnadzor obliges medical institutions to report adverse reactions to the agency.

Deadlines for sending information	What situations need to be reported?	Note
working days	unexpected reactions after taking drugs that led to situations that threaten the patient’s life or death.	The period must be calculated from the day when the minimum information was provided to the agency - about the adverse reaction, the suspected drug and the sender of the information
calendar	serious reactions that are undesirable, excluding those cases that initiated life-threatening conditions or led to the death of the patient; infection of a patient with an infectious disease as a result of taking a drug; ineffectiveness of drugs that are prescribed for particularly dangerous diseases that pose a threat to the patient’s life, vaccines against infections and to prevent pregnancy in all cases when the effect declared by the manufacturer from their use does not occur. There is no need to report to Roszdravnadzor if the clinical effect of taking the drug did not occur due to the individual characteristics of the patient; the occurrence of side and dangerous effects from taking the drug due to its overdose or drug abuse. This group also includes cases of exposure of a health care worker to a drug directly during the performance of work duties, as well as when someone deliberately administered or gave the patient a drug with the aim of causing harm to the patient’s health and life.
working days	cases where a case of individual intolerance to a drug has been recorded, if the patient received it on a preferential prescription under a trade name (details of the activities of the medical commission for prescribing such drugs are contained in the order of the Ministry of Health of the Russian Federation No. 502n dated 05/05/2012).	The period must be calculated from the day when the drug that caused the reaction was prescribed (by trade name)

For the purpose of control, medical commissions that prescribe subsidized drugs and identify cases of individual intolerance to them must report this to Roszdravnadzor from the moment it is prescribed to the patient. The drug must be prescribed by its trade name.

Thus, the authorized person for pharmacovigilance is responsible for sending notifications to Roszdravnadzor, for whom there are no requirements by law.

I'll put it in the folder

When does a clinic have the right to deviate from the standards? Four cases from practice and counter-arguments for inspectors to avoid sanctions from Roszdravnadzor - in the magazine “Deputy Chief Physician”.

The notification period is calculated from the day when the responsible person became aware of the following information about the undesirable effects of taking medications:

identification of the person or entity that identified the particular situation or adverse reaction;
information about the patient or other person who experienced the reaction/situation;
identification data about the medical product;
data on symptoms that appeared after taking the drug.

As part of internal monitoring of the effectiveness and safety of drugs, copies of notifications to Roszdravnadzor must be kept in patients' medical records.

In the future, the agency responsible for pharmacovigilance, Roszdravnadzor, publishes information on its portal about what decisions were made regarding the received requests.

This could be one of the following solutions:

The drug has been withdrawn from circulation for medical use.
The instructions for the medication have been amended accordingly.
Suspension of medication use.
Resumption of drug use for medical purposes.

Order of the Ministry of Health and Social Development No. 758n dated August 26, 2010 describes in detail the procedure for suspending the effect of medications.

Responsibility

Pharmacovigilance of the drug is mandatory for all subjects of drug circulation.

In order to implement the approved requirements for the pharmacovigilance system, personal liability has been established for officials who become aware of information about the dangers of a particular drug, the presence of adverse reactions and other situations, in the event that they did not report this to Roszdravnadzor.

Thus, for concealing information about the safety of drugs, if this information created a danger to the health and life of patients, nursing staff and doctors are liable under Art. 237 of the Criminal Code of the Russian Federation. In this case, medical workers can pay a large fine (up to 500 thousand rubles) or receive a punishment in the form of imprisonment for up to 2 years.

Medical institutions that do not send periodic reports to departments may be held administratively liable under Art. 19.7 of the Administrative Code, the fine is up to 5 thousand rubles.

Methods

Pharmacovigilance system uses different methods all over the world. The main one is the method of spontaneous messages.

Method of spontaneous messages in framaconadzor
The essence of the method	It involves immediately informing the agency responsible for state monitoring, Roszdravnadzor, about all adverse reactions of the drug during its use.
Purpose of the method	The purpose of the spontaneous reporting method is to identify unknown risks and new problems that are associated with the use of a particular drug. First of all, pharmacists, doctors and pharmacists learn about adverse reactions of a drug.
Method problem	Not all specialists inform Roszdravnadzor about complications and side effects that arise. The reason for this is: insufficient knowledge about the pharmacovigilance system; Lack of time; underestimation of the significance of the information received; fear of sanctions for identified adverse reactions.

Control at the MO level

Pharmacovigilance is carried out in medical institutions based on the following basic principles:

functioning of an effective drug safety system in each department;
implementation of a quality management system for maintaining medical records, including electronic ones;
a well-functioning system of continuity of medical care;
active interaction between doctor and patient;
control of the use of medications at all stages - from their storage and administration to the administration or administration of the drug to the patient.

Read more about how to organize pharmacovigilance in a medical institution in the appendices.

Is a medical organization obliged to monitor letters from Roszdravnadzor?

As part of pharmacovigilance, Roszdravnadzor periodically publishes monitoring data on its website in the form of information letters. The legal obligation of medical institutions to study and monitor them is not established.

This is due to the fact that information letters are not regulations, which means that they do not contain mandatory rules for medical institutions.

As a rule, in such letters, the agency invites organizations to check the presence of specific drugs in them that were recognized as unsafe based on monitoring results.

However, there is a legal contradiction. On the one hand, when a low-quality, unsafe and ineffective drug is introduced, in accordance with the Federal Law “On the Circulation of Medicines”, its manufacturer is responsible.

On the other hand, in accordance with the Federal Law “On Health Protection”, medical institutions are responsible for causing harm to the health and life of patients when providing medical care. In addition, medical institutions conduct pharmacovigilance of the drug and are responsible for using only high-quality and officially approved drugs within their walls.

Thus, despite the established manufacturer's responsibility, medical institutions should exercise reasonable caution and check information about the safety of certain drugs.

All the necessary information is presented on the Roszdravnadzor website, and, despite the absence of such an obligation, it is advisable to analyze this information by officials who are responsible for pharmacovigilance in a medical institution.

Keywords

EXPRESS REPORTING/ MESSAGE / NOTICE / ADVERSE EVENT / ADVERSE REACTION / PERIODIC REPORT / PERIODIC REPORT ON DRUG SAFETY / PERIODIC REPORT ON DRUG SAFETY/ PHARMACOVIGILANCE

annotation scientific article on fundamental medicine, author of the scientific work - Olefir Yu.V., Romanov B.K., Alyautdin R.N., Lepakhin V.K., Krasheninnikov A.E.

Summary. In connection with the implementation in Russia from January 1, 2018 of a risk-based approach to pharmacovigilance control, the responsibility of manufacturers and developers of medicines in terms of proper preparation and submission of reports increases. The purpose of the work is to assess the state of the system express reporting and periodic reporting on the safety of medicinal products in accordance with the current requirements of the legislation of the Russian Federation and the Eurasian Economic Union. The article continues a series of publications on recommendations for preparing pharmacovigilance reporting forms. The results of an assessment of the state of individual elements of the drug safety control system in Russia in terms of the preparation of reporting forms in accordance with current regulatory requirements of national and international legislation for holders of registration certificates of medicinal products for medical use and drug developers are presented. Conclusions: Recommendations for the proper preparation of periodic reporting are proposed. A range of problems are identified that require additional assessment, in particular the unsatisfactory state of the system of Regional Centers for Monitoring the Safety of Medicines in Russia. The article is addressed to clinical pharmacologists, pharmacovigilance commissioners, pharmacovigilance specialists, heads of medical and pharmaceutical organizations and researchers in the field of medicine.

Text of scientific work on the topic “Assessment of pharmacovigilance reporting in Russia”

ORIGINAL ARTICLES

https://doi.org/10.30895/2312-7821-2018-6-4-150-154

Assessment of pharmacovigilance reporting in Russia

Yu. V. Olefir1, *B. K. Romanov1, R. N. Alyautdin1, V. K. Lepakhin1, A. E. Krasheninnikov2, E. V. Shubnikova1

1 Federal State Budgetary Institution "Scientific Center for Expertise of Medical Products" of the Ministry of Health of the Russian Federation, Petrovsky Boulevard, 8, building 2, Moscow, 127051, Russian Federation 2 Autonomous non-profit organization "National Scientific Center for Pharmacovigilance", Bolshoy Boulevard, no 42, building 1, territory of the Skolkovo innovation center, Moscow, 143026, Russian Federation

Summary. In connection with the implementation in Russia from January 1, 2018 of a risk-based approach to pharmacovigilance control, the responsibility of manufacturers and developers of medicines in terms of proper preparation and submission of reports increases. The purpose of the work is to assess the state of the express reporting system and periodic reporting on the safety of drugs in accordance with the current requirements of the legislation of the Russian Federation and the Eurasian Economic Union. The article continues a series of publications on recommendations for preparing pharmacovigilance reporting forms. The results of an assessment of the state of individual elements of the drug safety control system in Russia in terms of the preparation of reporting forms in accordance with current regulatory requirements of national and international legislation for holders of registration certificates of medicinal products for medical use and drug developers are presented. Conclusions: Recommendations for the proper preparation of periodic reporting are proposed. A range of problems are identified that require additional assessment, in particular the unsatisfactory state of the system of Regional Centers for Monitoring the Safety of Medicines in Russia. The article is addressed to clinical pharmacologists, pharmacovigilance commissioners, pharmacovigilance specialists, heads of medical and pharmaceutical organizations and researchers in the field of medicine.

Key words: express reporting; message; notice; adverse event; adverse reaction; periodic report; periodic report on the safety of the drug; periodic report on the safety of the medicinal product; far-maconadzor

For citation: Olefir YuV, Romanov BK, Alyautdin RN, Lepakhin VK, Krasheninnikov AE, Shubnikova EV. Assessment of pharmacovigilance reporting in Russia. Safety and risks of pharmacotherapy. 2018;6(4):150-154. https://doi.org/10.30895/2312-7821-2018-6-4-150-154

*Contact person: Romanov Boris Konstantinovich; [email protected]

Assessment of Pharmacovigilance Reporting in Russia

Yu. V. Olefir1, *B. K. Romanov1, R. N. Alyautdin1, V. K. Lepakhin1, A. E. Krasheninnikov2, E. V. Shubnikova1

1 Scientific Center for Expert Evaluation of Medicinal Products, 8/2 Petrovsky Blvd, Moscow 127051, Russian Federation 2 Independent Noncommercial Organization "National Pharmacovigilance Research Center", 42/1, Bolshoi Blvd, Moscow 143026, Russian Federation

Abstract. The risk-based approach to pharmacovigilance control implemented in Russia since January 1, 2018 increases the responsibility of manufacturers and developers of medicines. The purpose of the work is to assess the system of Express reporting and Periodic reporting on the safety of drugs in accordance with the relevant requirements of the legislation of the Russian Federation and the Eurasian Economic Union. The article continues a series of publications on recommendations for the preparation of reporting forms on pharmacovigilance. The article presents the results of the assessment of the state of elements of the system of drug safety control in Russia in terms of the preparation of reporting forms in accordance with the current regulatory requirements of national and international legislation for holders of registration certificates of medicines for medical use and developers of medicines. Recommendations for proper preparation of periodic reporting are proposed. The range of problems requiring additional assessment, in particular, the state of the system of regional centers for monitoring the safety of medicines in Russia is highlighted. The article is addressed to clinical pharmacologists, pharmacovigilance

commissioners, pharmacovigilance specialists, heads of medical and pharmaceutical organizations and medical authors.

Key words: express reporting; adverse event; adverse reaction; periodic reporting; periodic safety update report; pharmacovigilance

For citation: Olefir YuV, Romanov BK, Alyautdin RN, Lepakhin VK, Krasheninnikov AE, Shubnikova EV. Assessment of pharmacovigilance reporting in Russia. "Safety"

i risk farmakoterapii = Safety and Risk of Pharmacotherapy. 2018;6(4):150-154. https://doi.org/10.30895/2312-7821-2018-6-4-150-154 *Contact person: Boris K. Romanov; [email protected]

The transition of the Russian Federation to the implementation, from January 1, 2018, of a risk-based approach to control and supervisory activities in the field of pharmacovigilance, has increased the number and importance of documentary checks, including quantitative and qualitative assessment of reporting, and minimizing risks in this part has become relevant for all subjects of the drug system security.

Preparation of express reporting and periodic reporting on the safety of a medicinal product is carried out on the basis of the Order of Roszdravnadzor dated 02/15/2017 No. 1071 “On approval of the Procedure for the implementation of pharmacovigilance” in the form and within the time limits given in the Decision of the Council of the Eurasian Economic Commission dated 11/03/2016 No. 87 “On approval of the Rules of Good Practice for Pharmacovigilance of the Eurasian Economic Union”1 by drug developers (organizations in whose name permission to conduct a clinical trial has been issued, or legal entities authorized by them) and holders of registration certificates (DRU) of all drugs registered in the Russian Federation (LP) for medical use.

Report forms are submitted by the DRU and drug developers in the recommended way - by sending them to the federal database “Pharmaconadzor” of Roszdravnadzor (for DRU) or to the database “MKILS” (Monitoring of Clinical Drug Trials) of Roszdravnadzor (for drug developers). If the cause of an adverse event during a clinical trial was the use of a registered drug, express reporting of this event is sent to

1 Decision of the Council of the Eurasian Economic Commission dated November 3, 2016 No. 87 “On approval of the Rules for Good Pharmacovigilance Practice of the Eurasian Economic Union.” Available from: http://docs. eaeunion.org/docs/ru-ru/01411948/cncd_21112016_87

drug developer into the Pharmaconadzor database of Roszdravnadzor.

An alternative way is to send reports to other databases, with the exception of situations with express reporting to independent ethical committees on the safety of clinical trials of drugs under development.

The purpose of the work is to assess the state of the express reporting system and periodic reporting on drug safety in accordance with the current requirements of the legislation of the Russian Federation and the Eurasian Economic Union (EAEU).

Research objectives: conducting a regulatory impact assessment; analysis of information sources for reporting; assessing corrective actions by regulators and industry; assessing the feasibility of preparing recommendations for proper reporting.

MATERIALS AND METHODS

Research materials - results of a survey of heads of medical and regulatory departments of pharmaceutical companies; administrative decisions posted in the State Register of Medicines from 01/09/2004 to 08/02/2018, the results of a survey of authors of medical journals, as well as regulatory legal acts and internal documentation of the regulatory authorities of Russia and the EAEU, domestic and foreign guidelines on methods for assessing the safety of drugs, scientific articles , federal databases on drug safety.

Information and analytical studies were carried out to assess the regulatory impact of current legislative requirements in the field of pharmacovigilance on the risks associated with the circulation of drugs for medical use, using methods of system analysis, expert surveys of opinion leaders, as well as methods of statistical data processing.

RESULTS AND DISCUSSION

To assess the regulatory impact, the results of a survey of 38 industry representatives and an analysis of 164 administrative decisions were assessed. It was found that in the first 9 months of 2018, the greatest difficulties arose with the preparation of periodic drug safety reports (DSRs) by the DRU. Half of the surveyed DRUs (19 respondents) noted the presence of negative expert opinions on the submitted PS, more than half of them (12 respondents) were domestic drug manufacturers. The results of the analysis of administrative decisions of the regulator indicate the predominant role of proactive industry sources - almost all decisions were prepared on the basis of letters from applicants and the Federal State Budgetary Institution "Scientific Center for Expertise of Medical Products" of the Ministry of Health of the Russian Federation (FSBI "NTsESMP" of the Ministry of Health of Russia).

A survey of drug developers showed that some organizations do not comply with regulatory requirements for submitting annual reports on the safety of drugs being developed. This applies exclusively to short-term clinical studies, for example when assessing bioequivalence. No other problems were identified with the preparation and submission of the required reports by drug developers.

An analysis of sources of information for reporting showed that an important source of information for assessing the benefit-risk ratio in PSA are publications in specialized media about the side effects of drugs and administrative decisions of foreign and international regulatory and scientific organizations regarding the safety of drugs. To assess the quality of this information, a survey was conducted among the authors of 4 medical journals specializing in drug safety issues.

The results of the survey showed a high level of understanding by the authors of medical journals of the required minimum amount of information sufficient for the high-quality operation of the pharmacovigilance system.

Another important source of information for the DRU is the system of spontaneous messages. These messages are sent to the Pharmaconadzor database of Roszdravnadzor by various categories of respondents (clinical pharmacologists, representatives of pharmaceutical companies, representatives of regional divisions of Roszdravnadzor, etc.). Traditionally, the highest quality information in spontaneous reports comes from specialized specialists - clinical pharmacologists and pharmacists of the Regional Centers for Drug Safety Monitoring (RMSC).

The results of a survey of RCMBLS employees conducted from July 19 to September 21, 2018 showed that 25 out of 61 RCMBLS listed on the Roszdravnadzor website2 had their email addresses changed, many centers no longer exist, 3 centers responded to requests to them within 3 or more months. The share of spontaneous messages from the RCMBLS is negligible. We can conclude that the RCMBLS system in Russia is currently virtually destroyed. At the same time, the proactive work of centers in certain regions of Russia continues to be carried out at a very high quality level, which makes it possible to rely on them when working with drug safety signals.

The assessment of corrective actions showed a high degree of readiness of Roszdravnadzor to improve the pharmacovigilance reporting system. Two lectures in the form of presentations were posted on the organization’s website, in which employees of the expert organization gave recommendations on risk assessment and the preparation of PSAs.

Of particular note is the importance for Russian pharmacovigilance of the international conference on pharmacovigilance with the participation of leading world-class specialists, first held on October 11, 2018 by Roszdravnadzor with the support of the Association of International Pharmaceutical Manufacturers and with the participation of specialists from the Federal State Budgetary Institution "NTsESMP" of the Ministry of Health of Russia and other expert organizations of Russia and countries EAEU. More than 200 industry representatives took part in the conference - primarily authorized persons for pharmacovigilance.

2 http://www.roszdravnadzor.ru/drugs/monitpringlp/documents/42074

An assessment of regulatory requirements for the preparation of express reporting and periodic reporting on drug safety indicates no changes in 2018 and the continued relevance of previously prepared recommendations.

When preparing periodic reports, the following recommendations should be followed.

1. The need for timely assessment of deadlines for reporting preparation. It is recommended to start preparing a few days before the end of the reporting period. As before, the preparation time is determined by the individual qualifications of the performer (including his understanding of current regulatory requirements, the ability to obtain all the necessary information and the ability to correctly apply the appropriate methods for working with this information), his workload, the volume and nature of the material being processed.

2. The need to check the compliance of the design, section titles, order of their presentation and content with the relevant current regulatory requirements (which may change).

3. The need to establish the conformity of information on drug safety during the reporting period with previously available information and, if required, to make a decision on making changes to the registration documentation based on new data.

4. The need to fill out all sections of the established reporting form using the current terminology codifier in Russian and universal methods of analysis to assess the degree of risk for all indications registered for a given drug in order to ultimately determine the benefit-risk ratio.

CONCLUSION

The results of the study allow us to evaluate the current state of the Russian system of express reporting and periodic reporting on drug safety as satisfactory. The proposed recommendations for the preparation of periodic reporting forms on pharmacovigilance meet the current requirements of the legislation of the Russian Federation and the EAEU.

Acknowledgments The work was carried out at the Federal State Budgetary Institution “NTsESMP” of the Ministry of Health of Russia within the framework of grant No. 064.44.2018 dated October 15, 2018 “Questioning of authors of medical journals. Development of recommendations for the preparation of periodic reports on drug safety.”

Acknowledgments. The data reported in this publication was supported by the Scientific Center for Expert Evaluation of Medicinal Products and was carried out as part of a publicly funded research project (public accounting No. 064.44.2018).

Conflict of interest. Authors declare no conflict of interest requiring disclosure in this article.

LITERATURE / REFERENCES

1. Snegireva II, Zatolochina KE, Ozeretskovsky NA, Romanov BK, Mironov AN. Pharmacovigilance of vaccines in Russia: legal regulation, features of development at the present stage. Gazette of the Scientific Center for Expertise of Medical Products. 2014;(4):27-31.

2. Makoveev AN, Berezina VS. Russian pharmacovigilance - 2016. Development and registration of medicines. 2015;(2):230-6.

3. Romanov BK, Alyautdin RN, Darmostukova MA, Glagolev SV, Polivanov VA. Standard form for a periodic report on the safety of a medicinal product. Safety and risks of pharmacotherapy. 2017;5(4):148-60.

4. Gildeeva GN, Yurkov VI. Pharmacovigilance in Russia: Challenges, Prospects and Current State of Affairs. J Pharmacovigil. 2016;(4):206. https:// doi.org/10.4172/2329-6887.1000206

5. Kuznetsov EA, Tikhonov SA, Berezina VS. Organization of a pharmacovigilance system in a pharmaceutical company. Development and registration of medicines. 2015;(4):172-80.

6. Gildeeva GN, Glagolev SV, Yurkov VI. Problems of drug safety control in the Russian Federation: the role of pharmacovigilance specialists. Bulletin of Roszdravnadzor. 2016;(5):114-8.

Olefir Yuri Vitalievich, Dr. med. Sciences, General Director of the Federal State Budgetary Institution “NTsESMP” of the Ministry of Health of Russia. ORCID: http://orcid.org/0000-0001-7652-4642

Romanov Boris Konstantinovich, MD. Sciences, Deputy General Director for Scientific Work of the Federal State Budgetary Institution “NTsESMP” of the Ministry of Health of Russia. ORCID: http://orcid.org/0000-0001-5429-9528 Alyautdin Renad Nikolaevich, Dr. med. sciences, prof., head of the Department for Expertise of the Safety of Medicines of the Federal State Budgetary Institution "NTsESMP" of the Ministry of Health of Russia. ORCID: http://orcid.org/0000-0002-4647-977X

Lepakhin Vladimir Konstantinovich, Dr. med. Sciences, prof., corresponding member. RAS, Chief Researcher of the Directorate for Expertise of Drug Safety of the Federal State Budgetary Institution "NTsESMP" of the Ministry of Health of Russia. ORCID: http://orcid.org/0000-0002-3706-7271

Krasheninnikov Anatoly Evgenievich, Ph.D. pharm. Sciences, General Director of the ANO “National Scientific Center for Pharmacovigilance”. ORCID: http://orcid.org/0000-0002-7791-6071 Shubnikova Elena Vladimirovna, Ph.D. honey. Sciences, senior analyst of the Department of Expert Analysis Methodology of the Directorate for Expertise of the Safety of Medicines of the Federal State Budgetary Institution "NTsESMP" of the Ministry of Health of Russia. ORCID: http://orcid.org/0000-0002-2888-5993

Article received 11/09/2018 After revision 11/26/2018 Accepted for publication 11/26/2018

7. Murashko MA, Parkhomenko DV, Asetskaya IL, Kosenko VV, Polivanov VA, Glagolev SV. The role and practice of pharmacovigilance in Russian healthcare. Bulletin of Roszdravnadzor. 2014;(3):54-61.

Yuri V. Olefir, MD, Dr. Sci. (Med.), General Director of the Scientific Center for Expert Evaluation of Medicinal Products. ORCID: http://orcid.org/0000-0002-4647-977X

Boris K. Romanov, MD, Dr. Sci. (Med.), Deputy General Director for Scientific Research of the Scientific Center for Expert Evaluation of Medicinal Products. ORCID: http://orcid.org/0000-0001-5429-9528 Renad N. Alyautdin, MD, Dr. Sci. (Med.), Professor, Head of the Division for Evaluation of Medicinal Products" Safety of the Scientific Center for Expert Evaluation of Medicinal Products. ORCID: http://orcid. org/0000-0002-4647-977X

Vladimir K. Lepakhin, MD, Dr. Sci. (Med.), Professor, corresponding member of the Academy of Sciences of Russia, Chief Research associate of the Division for Evaluation of Medicinal Products" Safety of the Scientific Center for Expert Evaluation of Medicinal Products. ORCID: http://orcid.org /0000-0002-3706-7271 Anatoly E. Krasheninnikov, Cand. Sci. (Pharm.), General Director of the National Pharmacovigilance Research Center ORCID: http://orcid.org/0000-0002-7791-6071

Elena V. Shubnikova, Cand. Sci. (Med.), Senior Analyst of the Department of Expert Analysis Methodology of the Division for Evaluation of Medicinal Products" Safety of the Scientific Center for Expert Evaluation of Medicinal Products. ORCID: http://or-cid.org/0000-0002 -2888-5993

1. Medicines in circulation in the Russian Federation are subject to monitoring of effectiveness and safety in order to identify possible negative consequences of their use, individual intolerance, warn medical workers, veterinary specialists, patients or animal owners and protect them from the use of such medicines .

(see text in the previous edition)

2. Pharmacovigilance is carried out by the relevant authorized federal executive body in the manner established by it by analyzing the information provided by the subjects of drug circulation on side effects, adverse reactions, serious adverse reactions, unexpected adverse reactions when using drugs, individual intolerance, lack of effectiveness of drugs, as well as about other facts and circumstances that pose a threat to the life or health of a person or animal when using medicinal products and identified at all stages of circulation of medicinal products in the Russian Federation and other countries.

3. Subjects of circulation of medicines, in the manner established by the authorized federal executive body, are obliged to report to the authorized federal executive body about side effects, adverse reactions, serious adverse reactions, unexpected adverse reactions when using medications, individual intolerance, lack of effectiveness of medications drugs, as well as other facts and circumstances that pose a threat to the life or health of a person or animal when using medicinal products and identified at all stages of circulation of medicinal products in the Russian Federation and other countries.

4. Holders or owners of registration certificates of medicinal products, legal entities in whose name permits to conduct clinical trials in the Russian Federation have been issued, or other legal entities authorized by them within the framework of ensuring the safety of medicinal products in the manner established by the relevant authorized federal executive body, are obliged receive, record, process, analyze and store messages received from subjects of medicines circulation and government authorities about side effects, undesirable reactions, serious undesirable and unexpected undesirable reactions when using medicinal products, about the peculiarities of their interaction with other medicinal products , individual intolerance, as well as other facts and circumstances that pose a threat to the life or health of a person or animal or that affect the change in the ratio of the expected benefit to the possible risk of using medications.

5. When identifying information about serious adverse reactions and unforeseen adverse reactions when using drugs, about the peculiarities of their interaction with other drugs, individual intolerance, as well as other facts and circumstances that affect the change in the ratio of the expected benefit to the possible risk of using drugs , holders or owners of registration certificates of medicinal products, legal entities in whose name permits to conduct clinical trials in the Russian Federation have been issued, or other legal entities authorized by them are obliged to take measures aimed at eliminating the negative consequences of the use of such medicinal products, preventing harm to life or human or animal health, their protection from the use of such drugs, for additional collection of data on the effectiveness and safety of such drugs.

6. For failure to report or concealment of information provided for in Part 3 of this article, holders or owners of registration certificates for medicinal products, legal entities in whose name permits to conduct clinical trials in the Russian Federation have been issued, or other legal entities authorized by them, as well as officials, to whom this information became known due to the nature of their professional activities, bear responsibility in accordance with the legislation of the Russian Federation.

7. When the authorized federal executive body receives, as part of its pharmacovigilance, evidence of non-compliance of a medicinal product with established requirements or upon receipt of information about the discrepancy between data on the effectiveness and safety of the medicinal product and the data on the medicinal product contained in the instructions for its use (including identified during the implementation of pharmacovigilance by control and supervisory authorities of foreign states), the authorized federal executive body, in the manner established by it, considers the issue of suspending the use of such a medicinal product.