Guidance

Guideline II Inspections

Updated 29 May 2024

Applies to England, Scotland and Wales

1. Monitoring of compliance by the VMD

Compliance monitoring relates to activities carried out by the VMD to ensure that a system of pharmacovigilance is in place within Marketing Authorisation Holders (MAHs). Methods used include examination of the Pharmacovigilance System Master File (PSMF), written procedures and safety reports, and monitoring prompt responses to requests for information. Deficiencies identified during compliance monitoring may lead to an inspection request. The aim of this process is to support companies to achieve compliance before regulatory action becomes necessary.

1.1 Qualified Person for Pharmacovigilance (QPPV)

The VMD will maintain a list of QPPVs. This list will include business address and contact details, including out of hours contact. MAHs should inform the VMD promptly of any changes in the name or contact details of the QPPV. Failure to inform the VMD of QPPV changes may be considered as non-compliance.

1.2 Availability of pharmacovigilance data

The VMD will monitor, through assessment of the PSMF and when inspections are carried out, that pharmacovigilance data are collated and accessible by the MAH at least at one location.

1.3 Expedited adverse event reporting

Requirements for expedited reporting of adverse events are given in section 2 of Guideline III Adverse event reporting. Methods available to the VMD for monitoring of compliance with expedited reporting of adverse events include:

• monitoring adverse event reports received from MAHs against other sources to determine complete failure to report

• monitoring the time between receipt by the MAH and submission to the VMD to detect late reporting

• monitoring the quality of reports, submission of reports judged to be of poor quality may result in the follow-up procedures of MAHs being scrutinised

• monitoring that all adverse events that are kept electronically comply with the requirements for electronic reporting set out in Guideline III Adverse Event Reporting

• checking interim and final reports of post-marketing surveillance studies to ensure that all qualifying adverse event reports have been submitted to the VMD within 30 calendar days
• at inspection there may be a review of a sample of reports on the MAH database to assess the quality of data, determine whether the relevant reports have been expedited, and to confirm that procedures are in place to follow up reports

1.4 Benefit-risk reports (BRRs) and signal notifications

MAHs should continuously monitor the benefit-risk balance of their products and submit an annual BRR to the VMD, as outlined in section 4 of Guideline IV Signal management, including benefit-risk reports.

One of the key responsibilities of MAHs is to immediately notify the VMD of any change in the benefit-risk balance of their veterinary medicinal products (VMPs). Any failure to do so may pose a significant threat to public or animal health. If a signal is identified suggesting a new risk or change of the benefit-risk balance of a product, the MAH must notify the VMD within 30 calendar days of it being identified. If an urgent safety signal is identified, the MAH should notify the VMD without delay and no later than the next working day for signals that require restrictions to be implemented or 3 days where no restrictions are deemed necessary (see section 2 of Guideline IV Signal management, including benefit-risk reports).

The VMD places great importance on compliance with BRR reporting. Non-compliance may include:

• complete non-submission of the BRR, late submission, or submission of a BRR that does not cover the correct time frame

• incorrect format of the document

• omission of information required in the BRR

• failure to inform the VMD of a change in the benefit-risk balance of a VMP within the specified timeframes

• previous requests from the VMD not addressed: submission of a report where previous requests from the VMD have not been addressed, for example, close monitoring of specific safety issues

1.5 Requests for information from the VMD

No fixed time frames are laid down in UK legislation or guidelines for responding to a request for information from the VMD. This reflects the fact that the appropriate time frame will depend mainly on the urgency of the pharmacovigilance issue and its potential impact on public or animal health. The VMD will ensure that requests for information from MAHs have a clear deadline when needed and this deadline should be appropriate to the complexity and urgency of the issue. The VMD will liaise with MAHs regarding the appropriate deadline, as required. Failure of MAHs to provide the necessary information/data within the deadline may be considered as non-compliance.

1.6 Submission of safety variations

As with responding to requests for information from the VMD, deadlines for submission of safety variations will depend on the urgency and potential public or animal health impact of the pharmacovigilance issue. In general, any variation requested should be submitted to the VMD within six months. Should the VMD require a variation to be submitted within a different timeframe the VMD will liaise with the MAH regarding the appropriate deadline. Failure of MAHs to submit the variation application within the deadline may be considered as non-compliance.

1.7 Post-marketing surveillance studies

Because of the objectives of post-marketing surveillance studies there is considerable potential for safety signals to arise or changes in the balance of benefits and risks of products to be identified. Therefore, reporting and submission to the VMD of interim and final study reports from such studies has an important role in protecting public or animal health. Where appropriate, the VMD will scrutinise protocols prior to the initiation of post-marketing surveillance studies. The VMD checks that relevant adverse event reports are submitted from those studies and monitors the submission of interim and final study reports. Guidance on post-marketing surveillance studies is available in Guideline V Post-marketing surveillance studies.

2. Pharmacovigilance Inspections

The VMD inspects all MAHs to ensure that they have the personnel, systems, and facilities in place to comply with their pharmacovigilance obligations as described in the VMR 2013 (as amended) Schedule 1 Part 8 paragraph 60A. Any MAH with a product authorised in GB can be subject to a pharmacovigilance inspection by the VMD, which may also include any of their partners or service providers.

2.1 Types of inspection

Pharmacovigilance inspections are scheduled according to the VMD’s risk-based approach, largely based on complexity and size of an organisation, products authorised, compliance history, and additional risk factors such as:

• the MAH has recently been, or is involved in, a merger or takeover process
• the MAH has changed their system significantly, for example, new database system, contracting out of reporting activities etc

Inspections will generally be routine but can also be targeted to MAHs suspected of being non-compliant.

2.2 Routine inspections

The MAH is notified of these inspections in advance. These may be inspections of the general pharmacovigilance system, or may be requested with one or more specific VMPs selected as examples for which specific information can be traced and verified through the various processes. This provides practical evidence of the functioning of the pharmacovigilance system of the MAH and their compliance with their regulatory obligations.

Where the pharmacovigilance system of a MAH has not been inspected previously, an inspection of the system will be performed within four years of placing the first VMP on the GB market. Where the system has previously been inspected, re-inspection will take place at intervals. If no critical findings are identified the frequency of inspection will be decided using the risk-based approach.

If an inspection results in a critical finding it is likely the MAH will be subject to a triggered re-inspection within 12 months, with a focus on the actions that were agreed following the last inspection.

2.3 Targeted inspections

Targeted inspections may be conducted when triggers are identified and the VMD determines that inspection is the appropriate course of action. Triggers which may result in a targeted inspection include:

• delays in carrying out, or failure to carry out, specific obligations or follow-up measures relating to the monitoring of product safety and efficacy

• delays in reporting

• incomplete reporting

• submission of poor quality or incomplete BRRs

• inconsistencies between reports and other information sources

• failure to communicate change in benefit-risk balance

• previous inspection experience

• information received from other authorities

• poor follow-up to requests for information from the VMD

The above are examples and other issues may trigger a targeted pharmacovigilance inspection. The presence of a trigger will not always lead to an inspection.

It is anticipated that the majority of triggered inspections will be announced. However, on occasions, it may be appropriate to conduct unannounced inspections or to announce an inspection at short notice.

2.4 Remote inspections

Routine and targeted inspections may be conducted by inspectors remotely. These inspections are conducted through a combination of review of requested documents, including evidence to support pharmacovigilance activities, and a method for interviews with relevant personnel. Logistical aspects of the inspection will be arranged with the MAH prior to the inspection. Should any significant issues be identified, that cannot be adequately reviewed during the remote inspection, it may be necessary to schedule an on-site inspection of the MAH’s pharmacovigilance system.

2.5 Inspection conduct

Inspection requests are prepared by the pharmacovigilance Inspector. As part of the inspection notification a number of documents will be requested. You must acknowledge you have received the notification and provide the requested documentation within the timeframe stated in the letter. Details of the relevant contact person for future correspondence about the inspection should be provided. If this is not the QPPV they should be made aware by the MAH of the inspection and be contactable during the inspection.

The inspection team will ask for additional documentation during the inspection. It is expected that any documents listed in the PSMF will be readily available for inspection. This includes procedure documents (such as standard operating procedures, working instructions, and guides), as well as outputs from pharmacovigilance activities such as safety meeting minutes, documented product safety reviews, audit risk assessments, and agreements in place with third parties and service providers.

The MAH should ensure access to internet and teleconference facilities, if required, throughout the inspection; as well as prompt access to printing and copying facilities, and access to all electronic documentation and systems including the safety database.

At the closing meeting the inspector will provide feedback and discuss any deficiencies and actions required with the MAH.

Each inspection will result in an inspection report. The inspection report will be made available to the MAH. Where an inspection reveals non-compliance the MAH will be required to prepare a corrective action plan to correct the non-compliances and avoid recurrence. The MAH may be required to provide evidence of the progress and completion of the action plan. There may be re-inspection at an appropriate time to verify the progress and success of these actions.

The results will be used to help MAHs improve compliance and may also be used as a basis for enforcement action.

3. Regulatory Action

When non-compliance with pharmacovigilance regulatory obligations is detected, the necessary action will be judged on a case-by-case basis. The action taken will depend on the potential negative public or animal health impact of non-compliance, but any instance of non-compliance may be referred for enforcement action.

In the event of non-compliance, regulatory options include the following:

• MAHs may be assisted to comply with the legislation through the provision of advice and guidance

• non-compliant MAHs may be inspected to determine the extent of non-compliance and then re-inspected to ensure compliance is achieved

• a formal warning may be issued reminding MAHs of their pharmacovigilance regulatory obligations

• an Improvement Notice may be issued

• the Marketing Authorisation (MA) may be suspended

• the MA may be revoked