Guidance

Pharmacovigilance systems, including Risk management

Updated 8 June 2022

Applies to England, Scotland and Wales

1. The Marketing Authorisation Holder (MAH)

The MAH must ensure that it:

• has a suitable pharmacovigilance system in place
• takes responsibility and liability for its veterinary medicines on the market
• can take appropriate action, when necessary

A qualified person responsible for pharmacovigilance (QPPV) must be permanently and continuously at the disposal of the MAH. We strongly recommended that an MAH, or group of MAHs using a common pharmacovigilance system, appoint one QPPV responsible for overall pharmacovigilance of all veterinary medicines for which the company, or group, holds MAs within GB. This person is ultimately responsible for all aspects of the pharmacovigilance system of a company, or group.

The MAH must ensure that the QPPV can fulfil their responsibilities and activities by providing the following:

• appropriate resources
• documented procedures
• communication mechanisms, including access to all sources of relevant information

The MAH must also implement mechanisms to keep the QPPV informed of:

• emerging safety concerns, and
• any other information affecting the evaluation of the benefit-risk balance of their veterinary medicines

This information may be from ongoing or completed clinical trials and other studies the MAH is aware of, including those carried out by organisations with whom the MAH has contractual arrangements and which may be relevant to the safety of the veterinary medicine.

The MAH must ensure that the QPPV has the authority to:

• implement changes to the MAHs pharmacovigilance system to promote, maintain and improve compliance
• provide input into the preparation of regulatory action in response to emerging safety concerns, for example, variations, urgent safety restrictions, and, if necessary, communication to the general public

The MAH should assess risks with potential impact on the pharmacovigilance system and plan for business contingency, including back-up procedures to cover, for example, non-availability of personnel, adverse event database failure, or failure of other hardware or software with impact on electronic reporting and data analysis.

2. The qualified person responsible for pharmacovigilance (QPPV)

The QPPV should be appropriately qualified, with documented experience in all aspects of pharmacovigilance so that they can be responsible for and perform the tasks of the post. If the QPPV is not a veterinarian, they should have access to a person qualified in veterinary medicine to assist with technical aspects of adverse event reports. MAHs must notify the VMD of changes to the name and contact details of the QPPV, including out-of-office hours details, or back-up procedures to ensure business continuity and continued fulfilment of pharmacovigilance obligations.

The QPPV:

• oversees the establishment and maintenance of a pharmacovigilance system which ensures that information about all adverse events which are reported to any personnel of the MAH, is collected, collated and made accessible at one or more named locations

• oversees the preparation for the VMD of the reports referred to in Part 8 of Schedule 1 of the VMR. Detailed guidance for the preparation of these reports is included in:

  • Adverse Event Reporting
  • Periodic Safety Update Reports
  • Post-Authorisation Safety Studies
• oversees the conduct of continuous overall pharmacovigilance evaluation during the post-authorisation period
• answers fully and promptly any request from the VMD for more information. This information, including volumes of sales or prescriptions of a veterinary medicine, aids the evaluation of the benefits and the risks of a veterinary medicine
• provides the VMD with any other information relevant to the evaluation of the benefits and risks of a veterinary medicine. This information may come from ongoing or completed post-authorisation safety studies, or from the actual use of a veterinary medicine. It may reveal evidence relating to the validity of the withdrawal period, or lack of expected efficacy or potential environmental problems

The QPPV should have oversight of the pharmacovigilance system in terms of structure and performance. They should be able to guarantee the pharmacovigilance system components and processes, either directly or through supervision. The oversight should include the functioning of the pharmacovigilance system, including:

• quality control and assurance procedures
• standard operating procedures
• database operations
• contractual arrangements
• compliance data, for example in relation to the quality, completeness and timelines for expedited reporting and submission of PSURs
• audit reports
• pharmacovigilance training of personnel

The role of QPPV involves extensive tasks, depending on the size and nature of the pharmacovigilance system and the number and type of veterinary medicines for which the MAH holds MAs. The QPPV may delegate specific tasks, under supervision, to appropriately qualified and trained individuals, for example, an expert on the safety aspects of certain veterinary medicines. The QPPV must keep system oversight and overview of the safety profiles of all veterinary medicines. Such delegation should be recorded. In case of absence of the QPPV, an adequately qualified person must undertake their responsibilities.

3. Contractual Arrangements

A MAH may transfer pharmacovigilance tasks and functions, including the role of the QPPV, to another person or organisation. The MAH remains responsible for the quality and integrity of all pharmacovigilance tasks carried out. The MAH must have detailed and clearly documented contractual arrangements with the other persons or organisations involved. They must provide information on such arrangements to the VMD on request. The contracted person or organisation should carry out quality assurance and control and accept audit by or on behalf of the MAH.

MAHs who co-market separately authorised veterinary medicines, which are identical in all aspects apart from their invented names, must have arrangements that include measures to avoid the duplicate submission of adverse events to the VMD.

4. The description of the pharmacovigilance system

All MAHs are required to have an appropriate system of pharmacovigilance in place. When applying for a Marketing Authorisation (M A), the Applicant should submit a Detailed Description of the Pharmacovigilance System (DDPS) in accordance with paragraph 2(3)(k), in Part 1 of Schedule 1 of the Veterinary Medicines Regulations and, where appropriate, a description of the risk management system. The DDPS should cover the Marketing Authorisation Application (M A A) in question, but where the details differ from the standard system, these particulars must be provided in a Product Specific Addendum.

An MAH may wish to compile the description of the pharmacovigilance systems for some or all of their products in a Pharmacovigilance System Master File (PSMF). In these cases, the MAH should provide a summary of the PSMF when applying for an MA, and should have the full PSMF available for inspection when required.

5. Requirements for DDPS

The DDPS provides evidence that the MAH has the services of a qualified person responsible for Pharmacovigilance (QPPV), and the necessary means for the notification of adverse events (AE). It is important to remember that the MAH is ultimately responsible for ensuring that all pharmacovigilance obligations are fulfilled, even if pharmacovigilance activities are subcontracted. If a MAH uses a third party, for example a contractor, licensing partner or other company, for processing pharmacovigilance information, this must be explained in the DDPS.

The document should describe all the essential elements of an effective pharmacovigilance system, but should not include unnecessary information. Step-by-step descriptions of procedures must be laid out in written procedures, for example standard operating procedures (SOPs), and these may be requested at any time by the VMD for inspection or assessment. However, they should not be included within the DDPS; inclusion of unnecessary information leads to the need for variations should that information be changed or removed at a later date. Updates to the information provided in the DDPS should be made in accordance with current legislation.

The DDPS, including proof of the availability of the services of the QPPV and the proof that the MAH has the necessary means for the collection and notification of any adverse event, should be provided in Part 1 of the MAA.

A statement, signed by both a representative of the MAH and the QPPV, declaring the availability of the QPPV and that the MAH has the necessary means for the collection and notification of any adverse events occurring either in GB or occurring outside GB should be provided. The representative/person signing the DDPS statement on behalf of the MAH should have the authority to do so. The person signing on behalf of the MAH should not be the same person as the QPPV, unless there is no other suitable person in the MAH.

The DDPS should be version-controlled and dated to enable the tracking of updates and corrections. The document should include the following elements, as applicable, and be set out in a structured manner consistent with this list. Additional important elements pertinent to a specific situation should be added.

5.1 QPPV

The name and contact details of the QPPV should be provided in section 8.3 of the MAA form. Companies might, for example, use a 24-hour telephone number through which the QPPV or their back-up can be reached, diverting it to the appropriate person according to availability.

A summary Curriculum Vitae (CV) of the QPPV with the key information relevant to their role, including main qualifications, training and experience. If the QPPV does not hold a veterinary qualification, the QPPV should have access to a veterinary surgeon to assist with veterinary assessment of AE reports. Note that lists of scientific publications unrelated to pharmacovigilance issues should not be included.

A summary of the job description of the QPPV, detailing the roles and responsibilities for pharmacovigilance. Any pharmacovigilance roles that are delegated to other persons should be listed. Individuals should not be identified by name but by their position in the organisation. Note that roles and responsibilities not related to pharmacovigilance should not be included. Roles to be included:

• establishment and maintenance of a pharmacovigilance system
• ensuring the accurate recording of AEs
• preparation of AE and Periodic Safety Update Reports (PSUR)
• conducting continuous/ongoing/periodic pharmacovigilance evaluation
• timely transmission of reports and provision of other information to the VMD, as required
• training, including general pharmacovigilance and specific pharmacovigilance activities

A description of the back-up procedure to apply in the absence of the QPPV. If a specific deputy is identified, this should not be by name, but by their position in the organisation. Note that the VMD may request the name and contact details of a deputy separately. This information would not be part of the DDPS.

5.2 Organisation

Identification and location of the company units, or other organisations, where the principal pharmacovigilance activities are undertaken, in particular those sites where the main databases are located, where adverse events are collated and reported, and where PSURs are prepared and processed for reporting to the competent authority. To include:

• the location and roles of each unit, for example, head office, local office, distributor/contractor etc., should be described, identifying which is responsible for data gathering, recording, assessment, reporting and archiving. Identification of affiliates may be made in a general sense, rather than affiliate-by-affiliate
• reporting interactions and the position of the QPPV or local pharmacovigilance contacts within the organisation must be described. The MAH should clarify whether the QPPV is directly employed by the MAH or subcontracted

The description should explain how the pharmacovigilance system described applies to the proposed MAH, particularly if the pharmacovigilance system spans a number of differently named subsidiaries and their parent company, and any one of those companies may be the MAH for a particular MAA. MAHs should provide a brief description of the organisation of the companies/subsidiaries/affiliates that may fulfil the role of MAH and are directed by the pharmacovigilance system described. It should be clear that the MAH named in the MAA is governed by the pharmacovigilance system. The description should be written so that it can be applied to any MAA, whatever the authorisation procedure or whichever of multiple MAHs is the MAH for a particular MAA.

High level organisation charts providing an overview of the pharmacovigilance units and organisations and illustrating the relationships between them. The charts should show the main reporting relationships with management and clearly show the position of the QPPV within the organisation. Individual names of people should not be included here. Licensing partnerships are usually product specific and should be indicated in a product specific addendum, in the MAA for that product, unless a partnership is a consistent feature of the company’s organisation, across most products.

Flow diagrams indicating the flow of safety reports of different sources and types. These should indicate how reports/information are processed and reported from the source, to the point of receipt by the competent authority. These should be limited to the major processes.

5.3 Procedures in place, which are documented in writing

An essential element of any pharmacovigilance system is that there are clear, written procedures in place. The following list indicates topics that should usually be covered by these written procedures. The DDPS should indicate for which of these topics there are written procedures in place; if any topic is not covered, an explanation should be provided. Copies of written procedures or SOPs should not be included, nor should the specific titles, numbers or version dates of the SOPs. A procedure may cover one or more of the topics or one topic may have one or more procedures depending on its complexity and the organisation of the company. Care should be taken to ensure that quality control and review are appropriately addressed in the various processes, and reflected in the relevant procedures:

• the activities of the QPPV and the back-up procedure to apply in their absence
• the collection, processing; including data entry and data management, quality control, coding, classification, veterinary review and reporting of adverse events. The process should ensure that reports of different types and from different sources are captured:
  • organised data collection schemes, unsolicited, clinical trials, literature
  • GB and non-GB, veterinarians and other health care professionals, animal owners, sales and marketing personnel, and other MAH personnel, licensing partners, competent authorities, others
• the follow-up of reports for missing information and for information on the progress and outcome of the cases
• detection of duplicate reports
• expedited reporting
• electronic reporting
• PSURs: The preparation, processing, quality control, review including veterinary review and reporting
• global pharmacovigilance activities applying to all products: Continuous safety profile of authorised veterinary products:
  • signal detection and review
  • benefit-risk assessment
  • communication with the VMD and animal health care professionals regarding changes to the benefit-risk balance of products and requests for information
• interaction between safety issues and product defects, specifically product defects that could lead to pharmacovigilance issues
• responses to requests for information from the competent authority
• handling of urgent safety restrictions and safety variations
• meeting commitments to the competent authority in relation to a marketing authorisation
• management and use of databases or other recording systems
• internal audit of the pharmacovigilance system
• staff training
• archiving

Copies of the global and GB procedures should be available within two working days after receipt by the MAH of a request from the VMD. Any additional local procedures should be available to respond to specific requests.

5.4 Databases

A listing of the main databases used for pharmacovigilance purposes, for example, compilation of safety reports, expedited/electronic reporting, signal detection, sharing and accessing global safety information, and brief functional descriptions of these should be provided, including a statement regarding the validation status of the database systems.

The means by which pharmacovigilance data is recorded should be described, whether paper records, spreadsheets, a database developed in-house or a proprietary database. The VMD is flexible as to whether a MAH has an electronic database, depending on the number of reports the MAH receives. However, we would prefer all MAHs to have some form of electronic storage for pharmacovigilance data, for example spreadsheets. Note that the description should be brief and technical specifications of the database should not be included. The person or group responsible for the operation and management of the database should be indicated.

A statement should be included regarding the compliance of the systems with the internationally agreed standards for electronic submission of adverse event reports. If the database is capable of assisting the compilation of safety reports and performing expedited and electronic reporting this should be described. The method of electronic reporting of cases occurring in both GB and outside GB should be indicated.

The MAH should describe the tools or approaches used for detecting signals.

It is also preferable that MAHs have databases for the control of submission of PSURs, for product information and for recording of sales information etc.

5.5 Contractual arrangements

Contractual arrangements with other persons or organisations involved in the fulfilment of pharmacovigilance obligations. Links with other organisations such as co-marketing agreements and contracting of pharmacovigilance activities should be outlined. The company should identify the major subcontracting arrangements it has for the conduct of its pharmacovigilance activities and the main organisations to which it has subcontracted these, in particular where the role of the QPPV, the electronic reporting of adverse events, the main databases, signal detection, or the compilation of PSURs is subcontracted.

A brief description of the nature of the agreements the company establishes with co-marketing partners and contractors for pharmacovigilance activities should be provided.

Since co-licensing or co-marketing arrangements are mainly product specific, any information on these may be provided in a product specific addendum, in the MAA. Likewise if subcontracting is product specific this should be indicated in a product specific addendum.

5.6 Training

Staff should be appropriately trained for performing pharmacovigilance related activities, taking into account their role within the company. This includes not only staff within the pharmacovigilance units but also staff who may receive or process safety reports, such as sales personnel, or field trial/clinical research staff. Describe the pharmacovigilance training given to all personnel, including contractors, who may be involved in pharmacovigilance. Personnel, should only be identified by their position in the organisation, not by name. Describe the type and frequency of training given, and the post holder who provides it. State where the training records of trainees and the CV and job description of the trainer are filed. Note that copies of personal training records should not be included in the DDPS.

5.7 Documentation

Provide a brief description of the locations of the different types of pharmacovigilance source documents, including archiving arrangements. Reference can be made to the organisation charts provided above.

Pharmacovigilance documentation should be stored securely. The location of documentation including original AE reports from the primary source, PSURs, Quality Control (QC) records relating to AE processing, SOPs and training records etc. should be identified. Also, the site where product sales figures can be accessed for pharmacovigilance should be identified. The length of time for which pharmacovigilance reports are archived should be indicated. The VMD would expect this to be at least for the life of the product plus some time to allow for expiry of the product. The VMD may request the identification of the post holders responsible for archiving, and a description of the validation and quality standards applied to archiving, but this should not form part of the DDPS.

5.8 Quality management system

Provide a brief description of the quality management system, making cross-reference to the elements provided under the above sections. Particular emphasis should be placed on organisational roles and responsibilities for the activities and documentation, quality control and review, and for ensuring corrective and preventive action.

A brief description of the responsibilities for quality assurance auditing of the pharmacovigilance system, including where appropriate auditing of sub-contractors, should be provided.

Note that, although it may be helpful, there is no requirement for certification to a particular standard. During the assessment of the DDPS additional information or assurance about the Quality Management system may be requested by the VMD, but it should not form part of the DDPS.

5.9 Supporting documentation

The MAH should ensure that the pharmacovigilance system is in place and documented. An essential feature of a pharmacovigilance system is that it is clearly documented to ensure that the system functions properly, that the roles and responsibilities and required tasks are clear to all parties involved and that there is provision for proper control and when needed change of the system.

5.10 Product specific addendum

Whilst not part of the main system description, this should be provided, if appropriate, in an Annex to the MAH DDPS. Risk management systems or post-authorisation requirements should be included here if appropriate. Where appropriate, a brief description should be given of the nature of any agreements for sub-contracting and co-marketing/co-licensing, specifying regulatory responsibilities and pharmacovigilance activities.

The MAH should identify precisely how the normal system is amended to accommodate the specific product. Requirements for PSMF and the PSMF summary

6. Requirements for PSMF and the PSMF summary

PSMF Summary

The PSMF Summary should be provided in Part 1 of the MAA and should include:

• The pharmacovigilance system master file reference number
• The pharmacovigilance system master file location
• Name, contact details and place of operation of the qualified person responsible for pharmacovigilance
• A signed statement from the marketing authorisation holder and the QPPV that the QPPV has the necessary means to fulfil the tasks and responsibilities required
• The type of record management system used for adverse events reports including the name of the database, if applicable

Content of the PSMF

The PSMF should describe the pharmacovigilance system that is in place at the current time. The sections in the main part of the PSMF should contain information that is fundamental for the description of the pharmacovigilance system, whereas the corresponding Annexes should include supplementary information for each section that may change frequently.

Section A: Information on the PSMF, including:

• PSMF reference number
• PSMF location

Section B: QPPV, assistant veterinary surgeon and back up procedures, including:

• Information on the QPPV including name, contact details and a signed statement from the marketing authorisation holder and the qualified person confirming that the qualified person concerned has the necessary means to fulfil the tasks and responsibilities required
• Documentation regarding arrangements for the assistance of a veterinary surgeon, if applicable, including the contact details
• A description of back-up arrangements that apply in the absence of the QPPV

Section C: Marketing Authorisation Holder information including:

• A detailed description of the organisational structure of the MAH, including a parent company or group of companies associated
• The position of the QPPV within the organisation

Section D: A description of the document management system including the record management system for adverse event reporting.

Section E: Quality Management System for pharmacovigilance activities, including:

• A description of the processes used for pharmacovigilance activities
• A description of the training management system in place
• A description of the system used for documenting or archiving information
• A description of the system for monitoring the performance of the pharmacovigilance system
• A description of the responsibilities for quality assurance auditing of the pharmacovigilance system including, where appropriate, auditing of subcontractors
• A list of audits associated with unresolved critical or major findings
• A description of the corrective and preventive action plan management and change management in place

Section F: A description of the contractual arrangements between marketing authorisation holders and third parties concerning pharmacovigilance activities, where applicable

The PSMF shall contain the following Annexes:

Annex I: a logbook containing records of all changes to the main part of the PSMF

Annex II: additional information regarding the QPPV, assistant veterinary surgeon, and associated back-up arrangements:

• curriculum vitae including information on qualifications and training of the QPPV and, if applicable, the assistant veterinary surgeon
• a description of the tasks and responsibilities of the QPPV
• list of the pharmacovigilance activities that have been delegated by the QPPV to third parties

Annex III: additional information on the marketing authorisation holder:

• a list of all veterinary medicinal products registered in GB and covered by the PSMF, including the international non-proprietary name (INN) of the active substances, if applicable, and the authorisation number
• a list of reference numbers for other PSMFs held by the same MAH, where applicable
• the name of the local representative for the purpose of receiving reports of suspected adverse events in GB, including their contact details and responsibilities, where applicable
• a list of the sites where pharmacovigilance activities are carried out

Annex IV: further details about the quality management system:

• a list of documents, policies, procedures and processes used for pharmacovigilance activities
• a list of all scheduled and completed audits including outstanding critical and major findings
• a list of performance indicators and how to use them, as applicable
• information on training plans and training records
• a list of risk management measures and the outcome of risk minimisation measures

Annex V: further information on contractual arrangements between marketing authorisation holders and third parties concerning pharmacovigilance activities:

• a list of the activities or services subcontracted by the MAH to third parties to fulfil pharmacovigilance obligations and information on who the activities or services are subcontracted to, including the name and address of any subcontractors, where applicable
• a list of the tasks of the QPPV that have been totally or partially outsourced and the information on who the activities or services are subcontracted to, including the name and address of the subcontractor(s), where applicable
• a list of existing contracts and agreements with third parties, where applicable, including the products and territories concerned

Annex VI: GB specific information

The VMD is prepared to accept the PSMF produced in line with the EU regulations. In this case the PSMF should include an additional annex covering GB specific information, this may include, but is not limited to:

• a signed statement from the MAH and the qualified person confirming that the qualified person concerned has the necessary means to fulfil the tasks and responsibilities required by the UK VMR 2013
• a list of all veterinary medicinal products marketed in GB, and covered by the PSMF, including the international non-proprietary name (INN) of the active substances, if applicable, and the authorisation number
• a list of contracts and agreements with third parties specific to veterinary medicinal products marketed in GB, not already included in Annex V
• a list of completed and scheduled audits, including outstanding critical and major findings, specific to veterinary medicinal products marketed in GB, not already included in Annex IV
• a list of UK specific written procedures covering pharmacovigilance activities, where applicable
• the name of the local representative for the purpose of receiving reports of suspected adverse events in the UK, including their contact details and responsibilities, where applicable

Where appropriate, information may be provided in the form of charts or flow diagrams.

7. Risk management

GB legislation requires applicants/MAHs to provide the VMD with a description of risk management systems, when appropriate, in accordance with paragraph 2(3)(k), Part 1 of Schedule 1 of the VMR.

The risk management system is defined as a set of pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to medicinal products, including the assessment of the effectiveness of those activities and interventions.

It is recognised that at the time of authorisation, information on the safety of a medicinal product is relatively limited. This is due to many factors including the limited representation of target animals, for example the number of animals, age, breeds etc, used in the pre-clinical and clinical development of the product. Risks of many potentially affected subpopulations remain to be identified during the clinical use of the product.

A veterinary medicine is authorised on the basis that in the specified indications, at the time of authorisation, the benefit-risk is judged positive for the target population, the user, the consumer of food from food producing animals as well as the environment. However, not all actual or potential risks are identified when an initial marketing authorisation is granted. Planning of pharmacovigilance activities will be improved if it were more closely based on product specific issues identified from pre- or post-authorisation data and from pharmacological principles.

Risk management is defined as the process, distinct from risk assessment, of weighing policy alternatives, considering risk assessment and other factors relevant to ensure quality, safety, including environmental safety, and efficacy of the veterinary medicine. Risk management should include, if needed, risk mitigation measures.