These Q&As are based on the Pharmacovigilance Inspectors Working Group’s interpretation of Veterinary Medicinal Products Regulation (Regulation (EU) 2019/6) and Commission Implementing Regulation (EU) 2021/1281. Q&As may refer to previous pieces of legislation and guidance but they are valid (unless they are marked as obsolete) by analogy.
Any pharmacovigilance activity which is outsourced by a marketing authorization holder (MAH) to a third party (contract acceptor) should be appropriately defined, agreed and controlled.
It is clearly stated in the legislation that a MAH may transfer any or all of the pharmacovigilance tasks and functions, including the role of the QPPV, to (an)other person(s) or organisation(s), but the ultimate responsibility for the fulfilment of all pharmacovigilance obligations and the quality and integrity of this always reside with the MAH [Commission Implementing Regulation (EU) 2021/1281, Article 2(7)]. In such cases, it is the responsibility of the MAH to ensure that detailed and clear documented contractual arrangements are in place between MAHs and persons or organisations involved in the fulfilment of pharmacovigilance obligations.
The MAH 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 subcontracted activities relate to the role of the QPPV, the electronic reporting of adverse events, the main databases, signal detection, literature search, etc.) and ensure those are clearly documented, detailed and up-to-date in the pharmacovigilance system master file [Regulation 2019/6, Article 77 (8) and (9)].
The pharmacovigilance system master file [Commission Implementing Regulation (EU) 2021/1281, Article 22] should contain all relevant information and documents concerning pharmacovigilance activities, including information on tasks that have been subcontracted to third parties. That information should contribute to the appropriate planning and conduct of audits by marketing authorisation holders and the supervision of pharmacovigilance activities by the qualified person responsible for pharmacovigilance. Furthermore, that information should enable competent authorities to verify compliance concerning all aspects of the system.
The main part of the pharmacovigilance system master file, shall contain in Section F a description of the contractual arrangements between marketing authorisation holders and third parties concerning pharmacovigilance activities, where applicable.
In Annex V of the pharmacovigilance system master file further information has to be included on contractual arrangements between marketing authorisation holders and third parties concerning the pharmacovigilance activities described in the main part:
(i) a list of the activities or services subcontracted by the marketing authorisation holder to third parties to fulfil pharmacovigilance obligations and information on who the activities or services are subcontracted to, including the name and address of the subcontractors, where applicable;
(ii) a list of the tasks of the qualified person responsible for pharmacovigilance referred to in Article 78 of Regulation (EU) 2019/6 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;
(iii) a list of existing contracts and agreements with third parties, where applicable, including the products and territories concerned.
Depending on the arrangements applicable for the pharmacovigilance system described in the pharmacovigilance system master file the respective information is generally to be compiled in three different lists, however for some pharmacovigilance systems not all information that is to be included in these three lists might be applicable, or some information included in the lists might be redundant (same information included in different lists). In case one or more of the respective lists are not applicable this should be stated in the respective section (e.g. Annex V.ii - no QPPV tasks outsourced). In case the respective lists (partly) contain the same information, it is possible to avoid redundant information in the lists by combining two or more lists, as long as the respective combined list is searchable and sortable in such a way that all information required in the different lists is easily retrievable from the combined list. If a combined list is used, cross-references are to be made in the respective Annexes to the combined list.
The MAH should have the means to verify the quality of the services given by the contract acceptor (and any other subcontractor), his capacity to carry out the assigned tasks and that he has implemented a quality assurance and quality control system. This verification may be carried out, for example, by on-site or “distant” audits. According to Commission Implementing Regulation (EU) 2021/1281, Article 8(2) any third party contracted to carry out pharmacovigilance activities in whole or in part, on behalf of or in conjunction with marketing authorisation holders, shall accept to be audited by or on behalf of marketing authorisation holders. The right of the MAH to perform audits should therefore be clearly stated in the contract. A description of the responsibilities for quality assurance auditing of the pharmacovigilance system and, where appropriate, auditing of subcontractors shall be included in Section D of the pharmacovigilance system master file [Commission Implementing Regulation (EU) 2021/1281, Article 22].
In order to ensure that pharmacovigilance activities managed by a MAH in collaboration with another party are carried out in compliance with existing legislation/guidelines, the agreement between the two parties should be formalized by means of a written contract.
A pharmacovigilance agreement is expected to be drawn up in the form of a contract, in accordance with the following recommendations:
Structure of the contract
Content of the contract
Contracts are expected to contain at least the following information:
The need for staff training is identified in legislation and guidance, as follows:
The above mentioned requirements can be interpreted as follows:
General considerations on training:
Staff involved to any extent in pharmacovigilance activities should be trained at an appropriate level and on a continuous base in pharmacovigilance. Moreover, training should always be provided after any change which affects the pharmacovigilance system (organization, procedures, etc).
The process of training for all staff should be described in writing (e.g. in an SOP).
Training of the QPPV:
An “appropriately qualified” QPPV should have a scientific background, best it would be a veterinarian with experience in the field of veterinary medicinal products (VMPs).
The QPPV is expected to have adequate knowledge in veterinary pharmacovigilance. This is normally achieved by attending a basic (initial) training followed by participation to (best external) training events on pharmacovigilance performed on a continuous base (the recommendation is at least once a year).
Documented evidence that the QPPV is keeping constantly updated on pharmacovigilance (legislation, procedures, guidelines, etc.) is also normally recognised appropriate as proof of the fulfilment of training requirements of the QPPV.
Training of pharmacovigilance-dedicated staff:
Pharmacovigilance dedicated staff is expected to have adequate knowledge in veterinary Pharmacovigilance. This is normally achieved by attending a basic (initial) training followed by participation to (best external) continued events on pharmacovigilance performed on a continuous base (the recommendation is at least once a year).
Documented evidence that pharmacovigilance dedicated staff is keeping constantly updated on pharmacovigilance (legislation, procedures, guidelines, etc.) is also normally recognised as appropriate as proof of the fulfilment of training requirements of pharmacovigilance-dedicated staff.
Training of other MAH staff*:
Initial training, followed by a periodic refresher training, is considered appropriate for all staff who could possibly encounter adverse events. The frequency of the periodic training should be evaluated on a case-by-case basis.
The above mentioned training has to include: (i) the recognition of adverse events including lack of efficacy, (ii) the collection of minimum information for adverse event reports and (iii) the importance of timely forwarding the information to the appropriate person.
(*e.g. sales representatives, telephone operators, product managers, field trial/clinical research staff, other MAH staff who could first come in contact with adverse events).
According to Commission Implementing Regulation (EU) 2021/1281, Article 2:
Therefore:
Documents demonstrating the title, the date, the lecturer, the participants, and the content of the training (e.g. training lecture notes, presentations or scripts for the participants) should be archived. The relation to pharmacovigilance for veterinary medicinal products should be apparent in the documents.
Not only the occurrence of a training should be documented, but also its effectiveness. Effectiveness could be documented, for example, by a test taken after the training. The training test and its outcome should be archived.
A document signed by the trainers, stating that the relevant trained staff has attended the training and understood its contents, should be available.
This whole training process should be described in writing (e.g. in a standard operating procedure).
The MAH should ensure that employees absent during a training event will get the opportunity to attend the same training on another date (as soon as possible). A system should be in place to keep track of the pending training. Training effectiveness should be ensured as mentioned below (question 4). This process should be described in writing (e.g. in an SOP).
According to VGVP Module on Pharmacovigilance systems, their quality management systems and pharmacovigilance system master files, section 2.5.5, there should be a process in place within the organisation to check that training results in the appropriate levels of understanding and conduct of pharmacovigilance activities for the assigned tasks and responsibilities, or to identify unmet training needs, in line with professional development plans agreed for the organisations as well as the individual staff members.
In case a given training has not proven to be effective for one or more participants, these should be retrained and should be given the possibility to clarify any residual doubts. Misunderstandings should be explained, all clarifications should be documented and the effectiveness of the training should be verified again. In the case of an initial training or a training on new job duties, the trainee can only start his activity when the training has been considered effective. This process should be described in writing (e.g. in an SOP).
According to Commission Implementing Regulation (EU) 2021/1281, Article 6 (2) marketing authorisation holders shall have a training management system in place for maintaining and developing the competences of their personnel. Information on training plans and records for pharmacovigilance activities and a reference to their location shall be kept in Annex IV, point (iv) to the pharmacovigilance system master file.
Documents demonstrating the title, the date, the lecturer, the participants, and the content of the training (e.g. training lecture notes, presentations or scripts for the participants) should be archived. The relation to pharmacovigilance for veterinary medicinal products should become apparent from the documents. Archiving can be paper based or it may be performed by electronic means. If electronic archiving of paper documents is chosen, a quality control of the process should be in place.
For data security and safe archiving, the same rules as for other pharmacovigilance documents apply.
Archiving should be performed according to a written procedure that also indicates where training records, CVs and job descriptions are filed. Records should preferably be maintained for as long as the pharmacovigilance system is in place and for at least 5 years after the system ceases to exist.
Not only the occurrence of a training should be documented, but also its effectiveness, which could be documented, for example, by a test which is taken after the training. The training test and its outcome should be archived.
A document signed by the trainers, stating that the relevant trained staff has attended the training and understood its contents, should be available.
This whole training process should be described in writing (e.g. in an SOP).
The MAH should ensure that the following evidence is readily available for inspection in order to give proof that staff involved in pharmacovigilance activities is properly trained:
An error in some national language versions of Articles 8(3), 22(3)(d)(ii) and 22(2)(e)(vi) of Commission Implementing Regulation (EU) 2021/1281 (EUR-Lex - 32021R1281 - EN - EUR-Lex [europa.eu]) has been identified, where the two different terms in the English version, "unresolved" and "outstanding" with reference to critical and/or major findings, are translated with either the same term/or having the same meaning in the national language versions. Until a translation-corrigendum of the language versions concerned is published and to ensure a consistent and harmonised implementation across all EU Member States of the aforementioned provisions of Commission Implementing Regulation (EU) 2021/1281, all relevant stakeholders are invited to consider the following.
Article 22(2)(e)(vi) of Commission Implementing Regulation (EU) 2021/1281 requires that "The main part of the pharmacovigilance system master file shall contain the following Sections: (…) Section E containing a description of the quality management system for pharmacovigilance activities, including all of the following: (…) (vi) a list of audits associated with unresolved critical or major findings".
The abovementioned reference to 'unresolved critical or major findings' should be interpreted as referring to audits during which critical or major findings were detected and for which the due date to implement the corrective and preventive action plan (CAPA) has already passed.
Pursuant to Article 22(3)(d)(ii) of Commission Implementing Regulation (EU) 2021/1281, Annex IV to the pharmacovigilance system master file shall contain "a list of all scheduled and completed audits including outstanding critical and major findings" (similar wording is included under Article 8(3) of Commission Implementing Regulation (EU) 2021/1281).
The abovementioned reference to 'outstanding critical and major findings’ should be interpreted as referring to audits during which critical and major findings were detected and for which the due date to address the corrective and preventive action plan (CAPA) has not passed yet.
Considering the above, it can be concluded that:
- Section E of the main part of the pharmacovigilance system master file shall list those audits with critical and major findings where the due date to implement the CAPA for the critical or major findings has already passed.
- Annex IV, point (ii) of the pharmacovigilance system master file shall include:
• A list of all scheduled and completed audits, including critical and major findings where the due date to implement the CAPA for the critical and major findings has not passed yet (outstanding critical and major findings).
Corrective and preventive action plans shall include findings from audits and inspections, in accordance with Article 9 of Commission Implementing Regulation (EU) 2021/1281.
The timeframe to implement the CAPA for critical and major findings should be clearly stated, and long-term or extended timelines should be duly justified.