Rules for good pharmacovigilance practice. What is pharmacovigilance, regulatory documents, regulatory measures. Description of pharmacovigilance systems

3.1.1. The master file of the pharmacovigilance system is intended to describe the pharmacovigilance system and documented confirmation of its compliance with the requirements of the legislation of the Member States, international treaties and acts constituting the law of the Union. The master file allows the marketing authorization holder to properly plan and conduct audits of the pharmacovigilance system, as well as inspections by authorized bodies of the Member States. The master file includes an overview of the pharmacovigilance system of the marketing authorization holder, which allows for its overall assessment by the authorized bodies of the Member States at the registration and post-registration stages.

3.1.2. Compiling a master file and updating the information contained in it allows the holder of the registration certificate and the authorized person for pharmacovigilance:

• make sure that the pharmacovigilance system is implemented in accordance with the requirements of the legislation of the Member States, international treaties and acts constituting the law of the Union;
• confirm the system’s compliance with current requirements; obtain information about system deficiencies or identify non-compliance;
• obtain information about the risks or ineffectiveness of certain pharmacovigilance activities.

3.1.3. The use of a master file helps optimize the process of proper system management, as well as improving the pharmacovigilance system. Requirements for the presentation of a summary of the marketing authorization holder's pharmacovigilance system in the form of a master file, as well as a chronology of changes made by the relevant authority, facilitate the planning and effective implementation of inspections based on the risk assessment method by the competent authorities of Member States.

3.2 Registration and maintenance of the master file

3.2.1. Location.

The master file of the pharmacovigilance system must be located in the territories of the Member States, either at the place where the main pharmacovigilance activities are carried out, or at the place where the qualified person is responsible for the implementation of pharmacovigilance, regardless of the format (paper or electronic). The competent authority of the Member State must be informed of the location of the master file, and must also be immediately informed of any changes in its location. The required information on the location of the master file includes an indication of the location (address) of the marketing authorization holder or a third party by agreement. This address may be different from the address of the applicant or marketing authorization holder, for example, if the address of a different office of the marketing authorization holder is specified, or if the main activity is carried out by a third party under an agreement. When determining the primary location for pharmacovigilance activities, the marketing authorization holder should consider the best location for the pharmacovigilance system as a whole. The marketing authorization holder must have appropriate justification for deciding on the location of the master file. In a situation where the main activity is carried out outside the Union or it is impossible to determine the main location, the default location of the master file is the place of activity of the authorized person for pharmacovigilance.

3.2.2. Transfer of responsibilities for the master file of the pharmacovigilance system.

3.2.2.1. The transfer or delegation of responsibilities and activities under the pharmacovigilance system master file must be documented and monitored to confirm that the marketing authorization holder has fulfilled its responsibilities. The authorized person for pharmacovigilance must be informed of changes made to the master file of the pharmacovigilance system in order to exercise his authority to make changes in order to improve the system. Types of changes that should be reported to the pharmacovigilance authority immediately:

• changes made to the pharmacovigilance system master file, or a change in its location, information about which must be reported to the authorized authorities of the Member States;
• adding corrective and (or) preventive measures to the master file of the pharmacovigilance system (for example, based on the results of audits and inspections) and managing deviations from the processes specified in the quality management system of the pharmacovigilance system;
• changes made to the information contained in the master file that meet the criteria for proper control of the pharmacovigilance system (within the limits of system capacity, operation and compliance);
• changes to the established agreement on the submission of the master file of the pharmacovigilance system to the authorized bodies of the Member States.

3.2.2.2. The Pharmacovigilance Authority must confirm in writing its notification of the following changes:

• inclusion of medicinal products in the pharmacovigilance system, for which an authorized person in pharmacovigilance is responsible;
• transfer of responsibilities for the pharmacovigilance system to an authorized person for pharmacovigilance.

3.3. Description of pharmacovigilance systems

The pharmacovigilance system master file must describe the pharmacovigilance system of 1 or more medicinal products of the marketing authorization holder. The marketing authorization holder may apply different pharmacovigilance systems to different categories of medicinal products. Each such system must be described in a separate pharmacovigilance system master file. These master files should generally cover all medicinal products of the marketing authorization holder for which a state registration certificate has been issued.

If the marketing authorization holder has more than 1 pharmacovigilance system, for example, specific pharmacovigilance systems for certain types of medicinal products (vaccines, sanitary products, etc.) or the pharmacovigilance system covers medicinal products of more than 1 registration authorization holder, it is submitted 1 pharmacovigilance system master file describing each system.

The marketing authorization holder must appoint an authorized pharmacovigilance person responsible for the creation and maintenance of the pharmacovigilance system described in the pharmacovigilance system master file.

If 1 pharmacovigilance system is used by several marketing authorization holders, each marketing authorization holder is responsible for having a pharmacovigilance system master file that describes the pharmacovigilance system for the products it produces. The marketing authorization holder may delegate, through a written agreement (eg, to a licensing partner or subcontractor), some or all of the pharmacovigilance activities for which the marketing authorization holder is responsible for proper performance. In this case, the master file of the pharmacovigilance system of the marketing authorization holder may be cross-referenced to the master file or part of the master file of the pharmacovigilance system managed by the system of the party to which the activity has been delegated on the basis of an agreement on access to this information by the marketing authorization holder and authorized bodies of the Member States. The marketing authorization holder must ensure that the contents of the reference files comply with the pharmacovigilance system applicable to the medicinal product.

Where appropriate, the appendix provides a list of pharmacovigilance system master files maintained by one marketing authorization holder. The attached information includes data on the location of the master files, information about the UPF and relevant medications.

IN brief information, submitted to the authorized bodies of the Member States, several locations of one pharmacovigilance system master file cannot be indicated.

When delegating activities related to the pharmacovigilance system and its master file, the marketing authorization holder is responsible for the pharmacovigilance system, providing information on the location of the pharmacovigilance system master file, maintaining the pharmacovigilance system master file and submitting it to the authorized bodies of the Member States upon request. There should be written agreements describing the roles and responsibilities for the pharmacovigilance system master file, its presentation and maintenance, and the implementation of pharmacovigilance.

When a pharmacovigilance system is used by multiple marketing authorization holders, it is recommended that the partners agree to jointly maintain the relevant sections within their master files in the system. The availability of the pharmacovigilance system master file for marketing authorization holders and its submission to the authorized bodies of the Member States should be specified in written agreements. It is important that the marketing authorization holder ensures that the pharmacovigilance system applied to their products meets the necessary requirements.

3.4 Mandatory information in the master file of the pharmacovigilance system

The pharmacovigilance system master file must include documents describing the pharmacovigilance system. The content of the pharmacovigilance system masterfile should reflect the availability of information on the safety of medicinal products registered in Member States. The master file must have a table of contents in order to provide orientation in the document.

3.4.1. Section of the master file about ULF.

Information about the ULF in the master file should include:

• a description of the responsibilities to ensure that the FDA has appropriate authority over the pharmacovigilance system to ensure, promote and improve compliance;
• a short summary with basic information about the role of the FFM;
• contact information about the ULF, which should include last name, postal address, telephone, fax numbers, email and work address;
• information on the application of standby agreements in the absence of FFM. In the case of delegation of certain tasks of the FFM to another contractor, a list of delegated tasks must be included in the annexes indicating a description of the delegated activity and the persons to whom it was delegated;
• a description of the qualifications and experience of the DFM relevant to pharmacovigilance activities.

3.4.2. Section of the master file on the organizational structure of the marketing authorization holder.

3.4.2.1. A description of the organizational structure of the relevant pharmacovigilance system of the marketing authorization holder must be provided. The description should provide a clear understanding of the organizations involved, the main units involved in pharmacovigilance, and the relationships between organizations and units relevant to the performance of pharmacovigilance activities. The pharmacovigilance system masterfile must contain the following information:

• address of the location where pharmacovigilance activities are carried out, including the collection and assessment of individual reports of adverse reactions, entry of reports into the safety database, preparation of periodic updated safety reports, identification and analysis of signals, maintenance of risk management plans, management of pre-marketing and post-registration studies and management of changes made to the safety information of the medicinal product.
• organizational structure of the marketing authorization holder, including an indication of the position of the FFM in the organization;

3.4.2.2. Section of the master file on outsourced pharmacovigilance activities.

3.4.2.2.1. The master file of the pharmacovigilance system must contain a description of the activities and (or) services to fulfill outsourced pharmacovigilance obligations.

3.4.2.2.2. The information in the section should contain confirmation of the relationship with other organizational structures (for example, an agreement on joint marketing of a medicinal product, an agreement on the implementation of pharmacovigilance activities by contractors, as well as other commercial agreements). The location and system of agreements in place for outsourced pharmacovigilance activities should be identified. The description of the system of agreements can be compiled in the form of a list or table. When describing the system of agreements in the form of a table, information is provided on the parties involved, the obligations assumed, the medicinal products for which pharmacovigilance is carried out and the territories of the Member States in which pharmacovigilance is carried out. When describing a system of agreements in the form of a list, it is structured by the types of services used (for example, the provision of medical information, audit services, provision of patient support programs, processing of research data), types of commercial agreements (agreement on the distribution of medicinal products, an agreement on joint marketing, an agreement on joint rights to a registration certificate, etc.) and types of technical support for pharmacovigilance activities (hosting computer systems on the provider’s servers, archiving and storing pharmacovigilance data, etc.). Copies of individual agreements are provided at the request of the authorized bodies of the Member States or during inspections and audits; their list is provided in the appendices.

3.4.2.2.3. The pharmacovigilance system master file must contain copies of signed agreements on such significant outsourced activities as:

• provision of pharmacovigilance services (authorized person for pharmacovigilance, entry of safety data, preparation of periodic updated safety reports, submission of individual reports of adverse reactions to in electronic format, safety data assessment, etc.);
• delegation of activities according to the master file of the pharmacovigilance system.

3.4.3. Section of the master file about sources of security data.

3.4.3.1. The description of the main departments concerned with the collection of individual reports of adverse reactions should include all parties responsible for the collection of reports received upon request and spontaneous reports of adverse reactions to medicinal products registered in the territories of Member States. The description should include the location of medical information as well as the organization's affiliated offices. This information can be compiled in the form of a list indicating the state, the nature of the activity and the drugs (if the activity depends on the type of drug). Information about third parties (licensing partners, local distribution or marketing agreements) is also included in the section that describes the agreements.

3.4.3.2. Sources of safety information should also include a list of ongoing studies, registries, support programs, or surveillance programs sponsored by the marketing authorization holder. The list should describe (at the global level) the status of each study or program, the relevant country, the drugs and the main objectives. Interventional and non-interventional studies should be listed separately according to the active ingredient of the medicinal product. The list must contain all studies (programs), ongoing studies (programs), and studies (programs) completed within the last 2 years.

3.4.4. Section of the master file on computer systems and databases.

3.4.4.1. The pharmacovigilance system master file should describe the location, functionality and operational responsibilities for the computer systems and databases used to obtain, verify, report safety information and evaluate its fitness for purpose.

3.4.4.2. Where a number of computer systems or databases are used, their applicability to pharmacovigilance activities should be described so that the extent of computerization within the pharmacovigilance system is clear. In addition, the validation status of key aspects should be described. functionality computer system, as well as change of control, trial design, backup procedures and electronic data archives necessary to comply with pharmacovigilance requirements, and available documentation. For paper-based systems (where the electronic system is used only for the urgent submission of individual adverse reaction reports), data management and the mechanisms used to ensure data integrity and access should be described.

3.4.5 Section of the master file about processes.

3.4.5.1. An important component of the pharmacovigilance system is the presence at the site of activity standard procedures in writing. Subsections 2.6, 2.9-2.12 of these Rules describe the required minimum set of written pharmacovigilance procedures. The pharmacovigilance system master file should describe the procedural documentation available (references to specific standard operating procedures, manuals, etc.), data types (e.g., individual adverse reaction case data type), and how records are maintained (e.g., database security, paper files at the place of receipt).

3.4.5.2. The master file of the pharmacovigilance system should include a description of the processes, procedures for processing and recording data when performing pharmacovigilance activities, which should include the following aspects:

• continuous monitoring of the benefit-risk ratio of the drug, the outcome of the assessment and the decision-making process on appropriate measures, the process of generating, verifying and evaluating signals, obtaining output data from safety databases, exchanging data with clinical departments, etc.;
• risk management system and monitoring the results of implementing risk minimization measures. If several departments are involved in this process, the order of their interaction is determined by written procedures or agreements;
• collecting, verifying, obtaining follow-up information, assessing and reporting information on individual cases of adverse reactions. The procedures under this section must clearly distinguish between local and international activities;
• planning, compiling and presenting periodic updated safety reports;
• providing consumers, medical professionals and authorized bodies of Member States with information about safety issues;
• introduction of safety-related changes to the SmPC and IMP (LP). Procedures should cover internal and external communication.

3.4.5.3. For each line of business, the marketing authorization holder must be able to provide evidence of the functioning of its system for making timely appropriate decisions and actions.

3.4.5.4. Data on other activities should be provided to demonstrate the existence of an appropriate quality assurance system in the pharmacovigilance system. Such data includes, in particular, data on the functions and responsibilities of the FFM, responding to requests from authorized bodies of Member States for the provision of information, literature searches, control of changes in safety databases, agreements on the exchange of safety data, archiving of safety data, pharmacovigilance audit, quality system control and training. During the review, you can use a table with all pharmacovigilance procedural documents (including their names and numbers).

3.4.6. Section of the master file on the application of the pharmacovigilance system.

The pharmacovigilance system master file must include confirmation of continuous monitoring of the functioning of the pharmacovigilance system, including monitoring of key results, as well as a description of monitoring methods and, at a minimum, contain:

• a description of the procedure for assessing the accuracy of individual reports of adverse reactions. Drawings (graphs) must be presented confirming the timeliness of the provision of information in accordance with the requirements of the legislation of the Member States;
• description of the benchmarks used to monitor the quality of information provided and pharmacovigilance activities. Such indicators include information received from competent authorities of Member States regarding the quality of adverse reaction reporting, PSARs or other data reported;
• analysis of the timeliness of submission of the PSAR to the competent authorities of the Member States (the latest data used by the marketing authorization holder to assess compliance with the requirements should be reflected);
• analysis of the timeliness of safety changes compared to established deadlines, as well as the date and description of required safety changes that have been identified but have not yet been submitted to the competent authority;
• where appropriate, review compliance with obligations under the risk management plan or other obligations or requirements relevant to pharmacovigilance.

It is necessary to describe and explain the purposes of the pharmacovigilance system. Where appropriate, a list of pharmacovigilance performance indicators should be attached to the pharmacovigilance system master file.

3.4.7. Section of the pharmacovigilance master file on the quality system.

This section provides a description of the quality management system within the organizational structure and the application of the quality system in pharmacovigilance.

3.4.7.1. Procedural documents.

A list of documented procedures and processes relevant to pharmacovigilance activities, indicating their relationship with other functions and approaches to evaluating procedures. The list should contain the document number, title, effective date (for standard operating procedures, work instructions, manuals, etc.), and a description of access to the documents. The standard operating procedures of service providers and other third parties should be specified.

3.4.7.2. Education.

A description of resource management during pharmacovigilance activities is provided:

• organizational structure with the number of people involved in the implementation of pharmacovigilance activities, including a link to the location of storage of qualification documents;
• list of personnel locations;
• a brief description of the training context, including a link to where training documents are stored;
• instructions for critical processes.

Personnel should be appropriately trained to carry out pharmacovigilance activities. This applies not only to personnel in pharmacovigilance departments, but also to persons who may receive safety communications.

3.4.7.3. Audit.

Information on the quality assurance audit of the pharmacovigilance system should be included in the pharmacovigilance system master file. The appendix should include a description of the method for planning pharmacovigilance system audits and reporting mechanisms, as well as a list of planned and completed pharmacovigilance system audits. This list should include the dates, scope and status of completion of service provider audits, specific pharmacovigilance activities or locations where pharmacovigilance functions are performed, and operational areas of interaction relevant to meeting obligations.

The pharmacovigilance system master file should also contain comments on audits during which significant results were obtained. This means that the list of audits performed should indicate the results that were assessed as significant or critical, as well as a brief description of the corrective or preventive action plan with deadlines for implementation. A link to the full audit report, documents with a plan of corrective and preventive measures must be provided.

Comments, corrective and preventive actions, as well as information about the location of the audit report should be included in the pharmacovigilance system master file until corrective and (or) preventive actions have been fully implemented, i.e. comments are deleted only after how the results of corrective actions will be demonstrated and/or evidence (including from an independent party) of significant system improvement will be provided.

As a means of managing the pharmacovigilance system and providing the basis for an audit or inspection, the pharmacovigilance system master file should also contain a description of the processes for recording, processing and eliminating deviations identified in the quality management system.

3.4.8. Appendix to the master file.

The appendix to the master file of the pharmacovigilance system must contain the following documents:

• a list of medicinal products that are registered by the holder of the marketing authorization in the Member States and in third countries, which are subject to the master file of the pharmacovigilance system, including the names of medicinal products, international nonproprietary names of active substances and the name of the state in which the registration certificate is valid, numbers of registration certificates .
• The list should be structured according to the active substances and, where appropriate, should indicate the existence of specific requirements for monitoring the safety of the medicinal product (for example, the introduction of risk minimization measures described in the risk management plan).
• In the case of joint pharmacovigilance systems, a list of medicinal products and marketing authorization holders that apply the pharmacovigilance system described in the pharmacovigilance system master file should be included, so that there is a complete list of medicinal products covered by the pharmacovigilance system master file;
• a list of contractual arrangements relating to delegated pharmacovigilance activities, including relevant medicinal products and territories;
• list of tasks delegated by the authorized person for pharmacovigilance;
• a list of all audits completed over a 10-year period and a list of planned audits;
• list of pharmacovigilance performance indicators (where applicable);
• a list of other pharmacovigilance system master files maintained by the marketing authorization holder (where applicable).

3.5 Change control, versioning and archiving

3.5.1. Authorized authorities of Member States may request information about important changes in the pharmacovigilance system, which may include, but are not limited to, the following changes:

• a) changes in the safety database(s) of the pharmacovigilance system, which may include changes in the database itself or in interconnected databases, changes in the validation status of the database, and changes in information about transmitted or transferred data;
• b) changes in the provision of significant pharmacovigilance services, especially if we're talking about important contractual arrangements for reporting safety data;
• c) organizational changes such as the acquisition of one company by another, merger, change in the location of pharmacovigilance activities or delegation (transfer) of management of the pharmacovigilance system master file.

3.5.2. Because the pharmacovigilance system master file includes lists of medicinal products and activities that may change periodically, marketing authorization holders should implement change control systems and develop reliable ways to remain aware of relevant changes so that the pharmacovigilance system master file can be reviewed appropriately. In addition, changes made to the pharmacovigilance system master file should be recorded so that a history of changes (including the date and context of the changes) is always available. Continuously updated information such as drug listings, standard operating procedures, or compliance data can be captured through a change history, which may include data from monitored systems (e.g. electronic systems data management or legal databases). Thus, it is possible to manage replaced versions of documents outside the text content of the pharmacovigilance system master file, provided that the history of changes is taken into account and they are presented to the authorized bodies of Member States upon request. Significant or important descriptive changes to the text content of the master file may require the creation of new version pharmacovigilance system master file.

3.5.3 Marketing authorization holders must justify the method chosen and develop documentation control procedures to properly manage the process of maintaining the pharmacovigilance system master file. The basic principle is that, while providing the basis for audits and inspections, the pharmacovigilance system master file contains a description of the pharmacovigilance system at the current time, but assessment of the functioning and focus of the pharmacovigilance system at previous stages may require additional familiarization with the system.

3.5.4. When making changes to the pharmacovigilance system master file, it is also necessary to take into account joint pharmacovigilance systems and delegated pharmacovigilance activities. Proper change control involves recording the date and context of notifications of changes made to the competent authorities of Member States, DFIs and third parties.

3.5.5. The pharmacovigilance system master file must be compiled in a readable and accessible form. It is necessary to provide a description of the archiving procedure on electronic and (or) printed media for the master file of the pharmacovigilance system.

3.6 Submission of the pharmacovigilance system master file

The PFA must have permanent access to the pharmacovigilance system master file. Authorized authorities of Member States should be provided with permanent access to the pharmacovigilance system master file upon request. The information in the master file of the pharmacovigilance system must be comprehensive, correct and reflect the current pharmacovigilance system at the current time, which means mandatory updating of the information in the master file and, if necessary, a revision taking into account the experience gained, technical and scientific progress, changes in regulations. The marketing authorization holder must ensure access to the master file of the pharmacovigilance system by the authorized bodies of the Member States within 7 working days after receiving the relevant request.

3.6.1. Format and structure

The master file of the pharmacovigilance system may be in electronic form, subject to the possibility of providing a clearly structured printed copy upon request of the authorized bodies of the Member States. In any format, the master file of the pharmacovigilance system must be in a readable, complete and accessible form, ensuring the ability to evaluate all documents and traceability of changes. It may be necessary to restrict access to the pharmacovigilance system master file to ensure adequate control of its contents and to allocate responsibilities for managing the pharmacovigilance system master file (in the context of change control and archiving).

3.7 Responsibilities of participants in the pharmacovigilance system

3.7.1. Registration certificate holders.

3.7.1.1. Marketing authorization holders must develop and implement a pharmacovigilance system for the purpose of monitoring and monitoring one or more medicinal products. They are also responsible for creating and maintaining a pharmacovigilance system master file that records pharmacovigilance activities for one or more registered medicinal products. The marketing authorization holder must appoint one DFM responsible for the creation and operation of the pharmacovigilance system described in the pharmacovigilance system master file.

3.7.1.2. When submitting an application for registration of a medicinal product, the applicant must have at his disposal a description of the pharmacovigilance system that will operate in the territory of the Union or the territory of individual Member States. During the assessment of an application for registration, the applicant may be required to provide a copy of the pharmacovigilance system masterfile for review.

3.7.1.3. The marketing authorization holder is responsible for creating a master file of the pharmacovigilance system in Member States and registering the location of the master file with the competent authorities of Member States when submitting an application for registration of a medicinal product. The pharmacovigilance system master file must describe the current pharmacovigilance system. You can include information about system components that will be implemented in the future and that should be listed as planned rather than implemented or operational.

3.7.1.4. The work of creating, maintaining and submitting a master file of the pharmacovigilance system to the authorized bodies of the Member States may be transferred to a third party, but the holder of the marketing authorization retains full responsibility for compliance with the requirements of the legislation of the Member States, international treaties and acts constituting the law of the Union. Maintenance of the pharmacovigilance system master file in a valid and accessible state (permanent access for audit and inspection) can be delegated, but the marketing authorization holder permanent basis bears responsibility for ensuring the performance of this function at a level that meets the requirements of the legislation of the Member States, international treaties and acts constituting the law of the Union.

3.7.1.5. In the event of a change in the SFM or the corresponding contact information, as well as the location of the master file of the pharmacovigilance system, the holder of the marketing authorization submits an application to the authorized bodies of the Member States to make the appropriate changes. Marketing authorization holders are responsible for updating the information about the SFM and the location of the pharmacovigilance system master file.

3.7.2 Authorized bodies of the Member States.

3.7.2.1. The competent authorities of the Member States are responsible for monitoring the pharmacovigilance systems of marketing authorization holders. The complete pharmacovigilance system master file can be requested at any time (for example, when questions arise about the pharmacovigilance system, or the safety profile of a medicinal product, or in preparation for an inspection). Information about changes to the pharmacovigilance system summary or the content of the pharmacovigilance system master file is also used during the planning and conduct of the inspection.

3.7.2.2. Authorized authorities of Member States exchange information on pharmacovigilance systems, including for the purpose of transferring data to national inspection programs developed on the basis of risk analysis. Inspectors from the competent authorities of Member States report non-compliance with mandatory requirements, including the requirements for the pharmacovigilance system master file and the pharmacovigilance system.

3.8 Availability of the pharmacovigilance system master file

3.8.1. The master file of the pharmacovigilance system is maintained in a valid and accessible state for the authorized person for pharmacovigilance. It must also be available for inspection at all times, whether prior notice has been given or not.

3.8.2. The marketing authorization holder maintains and provides, upon request of the authorized body of the Member State, a copy of the master file of the pharmacovigilance system. The marketing authorization holder shall provide a copy of the master file within 7 working days of receipt of the relevant request. The master file of the pharmacovigilance system is presented in readable form in electronic format or on paper.

3.8.3 If the same pharmacovigilance system master file is used by more than one marketing authorization holder (in the case of using common system pharmacovigilance), the corresponding master file of the pharmacovigilance system must be available for each of them in such a way that each of the marketing authorization holders has the opportunity to submit the master file to the competent authority of the Member State within 7 working days after receiving the relevant request.

3.8.4. The pharmacovigilance system master file is generally not requested during the assessment of new applications for registration of a medicinal product (i.e. prior to registration of the medicinal product), but may be requested in special cases, in particular in the case of introduction new system pharmacovigilance or when identifying problems with the safety of a medicinal product or questions regarding compliance with the requirements of the legislation of a Member State and international treaties and acts constituting the law of the Union on pharmacovigilance.

GOOD PHARMACOVIGILANCE PRACTICES IN THE US AND EUROPEAN UNION

Merkulov V.A., Bunyatyan N.D., Pereverzev A.P.

Federal State Budgetary Institution "Scientific Center for Expertise of Medical Products" of the Ministry of Health Russian Federation, Moscow

Summary: The article presents the results comparative analysis Good Pharmacovigilance Practices (GVP) developed by experts from European Union (EU) and US regulatory authorities. EU GVPs have been shown to cover almost all possible aspects of pharmacovigilance. It is noted that the disadvantages of GVP EU are difficulties in correctly understanding and interpreting some definitions and processes, as well as the difficulty of implementing in practice a number of provisions, mainly related to the organization of a quality management system, including audits and inspections. The use of GVP EU is recommended as a basis for the development of domestic GVP Rules.

Key words: good pharmacovigilance practice, European Union, EU, USA.

GOOD PHARMACOVIGILANCE PRACTICE IN THE UNITED STATES AND THE EUROPEAN UNION

Merkulov V.A., Bunyatyan N.D., Pereverzev A.P.

Federal State Budgetary Institution "Scientific Center for Expert Evaluation of Medicinal Products",

Ministry of Health of the Russian Federation, Moscow

Summary: The article presents the results of a comparative analysis of Good pharmacovigilance practices (GVP), developed by experts of the regulatory bodies of the European Union (EU) and the United States. It is shown that the EU GVP cover almost all possible aspects of pharmacovigilance. It is noted that the disadvantages of EU GVP are difficulties in the correct understanding and interpretation of certain definitions and processes, as well as the complexity of the implementation in practice of a number of provisions, mainly related to the organization of the quality management system, including audit and inspection. As the basis for development of the Russian Rules GVP is recommended to use the GVP EU.

Key words: Good pharmacovigilance practices, GVP, European Union, EU, United States.

European Union (EU). To carry out this assessment, methods of comparative analysis and analytical and synthetic information processing were used

In March 2005, the US Food and Drug Administration (FDA), as part of its efforts to develop risk management measures for the pharmaceutical industry in the use of drugs (drugs) and immunobiological medicinal products (IMPs), prepared “ Guidance for the Pharmaceutical Industry. Rules for good pharmacovigilance practices and pharmacoepidemiological assessment" (Guidance for industry. Good Pharmacovigilance Practices and Pharmacoepidemiology Assessment). This document is advisory in nature and reflects the FDA's current point of view regarding ways to identify drug safety signals, their analysis, pharmacoepidemiological assessment and development of a pharmacovigilance plan.

The regulations prepared by FDA staff contain the following sections:

Good Reporting Practices;

Characteristics (criteria) of a well-prepared report on complications of pharmacotherapy (Good Case Report);

Methods for generating and analyzing a series of reports on complications of pharmacotherapy (including using mathematical and statistical tools - the so-called. data mining);

Criteria for drug safety signals that require further study;

Examples of non-randomized observational study designs aimed at studying drug safety signals (incl.

pharmacoepidemiological, registers, etc.);

Interpretation of the data obtained: calculation of the frequency of development of new cases of HP (incidence rate) and reporting rate (reporting rate);

Approaches to preparing a pharmacovigilance plan.

The rules of good pharmacovigilance practice developed by the FDA are advisory and subjective in nature (the use of alternative forms and methods of reporting that do not contradict federal legislation is allowed with the consent of the agency expert), which compensates for the absence of such sections as quality criteria for the functioning of the pharmacovigilance system, audit of the pharmacovigilance system, templates for documents on drug safety submitted to regulatory authorities.

GVP of EU countries

In December 2010, new legislation in the field of pharmacovigilance came into force in the European Union (Regulation (EU) No 1235/2010 and Directive 2010/84/EU), according to which a regulatory network is being formed in the EU, consisting of the responsible authorities of the countries - members, the European Commission and the European Medicines Agency (EMA), which has a coordinating role.

The department within the EMA responsible for the functioning of the pharmacovigilance system and assessing the risks associated with the use of drugs is the Pharmacovigilance Risk Assessment Committee (PRAC).

The key package of documents in this legislation is the Rules of Good Pharmaceutical Practice

pharmacovigilance, developed by a commission of experts from the EMA and EU member states to ensure the functioning of the pharmacovigilance system in the EU.

Structurally, the Rules of Good Pharmacovigilance Practice are divided into 16 modules (description of the main pharmacovigilance processes

zora) and recommendations (considerations) prepared for individual medical products or aimed at specific population groups (will be published as they are ready, one after another). The list and summary of modules and recommendations of the GVP of EU countries are presented in Table 1.

Table 1. Modules of the EU Good Pharmacovigilance Practice Rules

Module number Short description module

Module I Pharmacovigilance systems and quality criteria for their functioning

Module II Master File

Module III Inspections

Module IV Audit of the pharmacovigilance system

Module V Risk Management Systems

Module VI Methods for handling reports of adverse reactions (management and reporting)

Module VII Periodic Safety Report (PSR)

Module VIII Post-marketing safety studies

Module IX Signal Control

Module X Additional Monitoring

Module XI Public participation in pharmacovigilance

Module XII Ongoing pharmacovigilance process, methods for assessing the benefit-risk relationship of pharmacotherapy, the process of taking administrative measures, planning and organizing public relations

Module XIII Work on the development of this module (incident management) has been discontinued. Available information materials are included in Module XII

Module XIV International cooperation

Module XV Organization of communications in the field of drug therapy safety

Module XVI Risk Mitigation Measures: Selecting Tools and Performance Indicators

Appendix I Definitions

Appendix II Templates for ESOPs and calls to healthcare professionals (Direct healthcare-professional communication)

Annex III Other pharmacovigilance guidelines

Appendix IV of the Guidelines International Conference on Harmonization of technical requirements for registration of pharmaceuticals for human use (International conference on Harmonization of Technical Requirements for registration of Pharmaceuticals for Human Use, ICH) on pharmacovigilance

The rules of good pharmacovigilance practice in the EU countries cover almost all possible aspects of pharmacovigilance, however, a number of provisions, such as methods for assessing the benefit-risk relationship of pharmacotherapy, the organization of a quality management system, including audits and inspections, are insufficiently comprehensive.

worked (are in the process of discussion) and may present difficulties in implementation in practice.

Comparative analysis of US and EU GVP

The results of the comparative analysis of the US and EU ESD Rules are systematized and presented in Table 2.

GVP USA GVP EU countries

Legal status of the document

Recommendatory (it is possible to use alternative approaches, if they do not contradict existing legislation) Mandatory (strict compliance with the norms and rules specified in the documents is necessary)

Terminology

Contains a small number of definitions necessary to understand the Rules. Worked out in detail; contains a large number of terms and definitions.

Deadlines for reporting and reporting on incidents

Not specified Specified

Criteria for the quality of functioning of the pharmacovigilance system

No Specified

Methods for analyzing the benefit-risk relationship of pharmacotherapy

No (introduced in Q4 2014)

Pharmacovigilance system audit

No Description of the regulatory framework, organizational structure and processes in the pharmacovigilance audit system

Post-registration studies of drug safety

Criteria for signaling the safety of drugs that require additional observational studies (including pharmacoepidemiological) and examples of their design are presented. Description of cases in which post-registration clinical studies are necessary, their goals, methods, design, as well as the list and structure of documents necessary for the study

Templates for documents on drug safety submitted to regulatory authorities

Ways to communicate effectively

Management of risks

Yes (one of three documents included in the risk management program developed by the FDA under the Prescription Drug Use Act (PDUFA III) for the pharmaceutical industry) Yes

The international cooperation

Not provided Provided

Table 2. Differences between US and EU GVP Rules

From the data presented in Table 2 it is clear that there are certain differences between the GVP Rules applied in the US and the EU. Thus, the GVP Rules proposed by FDA specialists are rather advisory and subjective in nature, while similar Rules applied in the EU are mandatory and describe in detail all activities carried out as part of drug safety monitoring.

The advantages of both versions of the GVP Rules are the possibility of creating a new or increasing the efficiency of an existing drug safety monitoring system; facilitating communications and mutual understanding between all subjects of drug circulation; unification of quality requirements for information provided by registration certificate holders and the functioning of the drug safety control system; increasing the safety of pharmacotherapy by taking prompt and risk-appropriate regulatory measures aimed at completely eliminating or minimizing the severity of consequences.

The main general disadvantages of the US and EU GVP Rules include difficulties in correctly understanding and interpreting some definitions and processes, as well as difficulties in implementing a number of provisions in practice. This imperfection of the GVP Rules, which must be taken into account when preparing and developing them for Russia, is caused by the fact that at the current stage of pharmacovigilance development it is not possible to create a universal algorithm or standard operating procedure (SOP) for analyzing drug safety documentation. In many ways

the results of this work depend on the qualifications of the expert, the chosen analytical approach, as well as the reliability and quality of the information used.

Another problem, an effective solution to which is not presented in foreign Rules, is the insufficient level of reporting on cases of drug complications (in English literature to denote this concept the term underreporting is used).

The third problem of the Rules can be called the insufficient development of methods for analyzing the benefit/risk ratio of pharmacotherapy and determining the degree of reliability of the cause-and-effect relationship between the use of drugs and adverse reactions. The currently available methods for assessing the potential benefits and possible risks when using drugs cannot be called absolutely objective, universal (applicable for any group of drugs and patients) and “transparent”.

It should be especially noted that there is still no consensus among subjects of drug circulation (primarily between regulatory authorities and pharmaceutical companies) regarding the need and possibility of using a single generally accepted model for assessing the benefit/risk ratio, which includes, in addition to the method itself, an algorithm analysis, regulatory framework and special guidelines.

Insufficient attention within the framework of the Rules for Quality Pharmacovigilance Practice is paid to such aspects of pharmacovigilance as pharmacoepidemiology, work with data sources, and the use of communication and information technologies.

The shortcomings described above are global, require further study and cannot be resolved at this time.

Ways to solve them should be the improvement of computer technologies aimed at searching and processing data (data mining); training of practical healthcare specialists in the basics of pharmacovigilance, methods of identifying, verifying and sending reports of ADRs, as well as localization and adaptation

Literature

tion of the Rules to Russian conditions.

Conclusion

As a result of the study, the advantages and disadvantages of the Rules for Qualitative Pharmacovigilance Practices of foreign regulatory authorities were identified, and proposals were made for the implementation of ERM rules in Russia to improve the qualitative and quantitative indicators of the functioning of the drug safety monitoring system.

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Ministry of Health of the Russian Federation

Situational task No. 5

The holder of the registration certificate conducts a mandatory non-interventional study of the drug “PV” in everyday clinical practice in patients with arterial hypertension and with a concomitant diagnosis of pyelonephritis. The estimated sample is 220 people. According to the protocol, the established period of time for conducting the study is 1 year. The purpose of the study was to assess the safety of the use of drugs in everyday clinical practice in patients with a concomitant diagnosis of pyeloniphritis. What basic documentation must be provided to the designated regulatory authority for the entire study period?

Situational task No. 6

Clinical studies involve 20 people of fertile age of both sexes. What activities need to be planned in a prevention program?

Situational task No. 7

During post-marketing monitoring of the drug, a new safety issue was identified. National regulatory authorities have informed the relevant marketing authorization holder that a decision has been made to include this drug in the list of medicinal products subject to additional monitoring. What is the marketing authorization holder obliged to do in this case?

Situational task No. 8

The marketing authorization holder has received a communication from a physician of a patient participating in the WW-3-33 clinical trial. The report refers to the development of an adverse reaction in a patient to the drug WW, produced by marketing authorization holders. Is this message spontaneous?