2020-21 MHRA PV Inspection Metric Report
From 01 April 2020 to 31 March 2021, the MHRA’s Good Pharmacovigilance Practice Inspectorate (GPvP) conducted 37 pharmacovigilance (PV) inspections on 36 marketing authorisation holders (MAHs) to evaluate its PV processes and compliance with existing EU and national PV regulations. The 2020/21 report has been released by the MHRA with the intention to inform the public and have those in the industry evaluate and consider improvements within their own organisation[1].
Since the UK’s exit from the European Union (EU) on 31 January 2020, GPvP inspections were conducted in accordance with the EU regulations and guidance during the transition period, up until 31 December 2020. From then on, the inspections were conducted in accordance with Human Medicines Regulations 2012 (as amended) and GVP Module III (as modified for UK MAHs). All 37 PV inspections were carried out remotely.
Overview of Inspections
A total of 37 inspections were conducted on 36 organisations during the reporting period, 16 of which were planned as routine inspections, 16 were conducted due to intelligence received by the GPvP and five were conducted due to a previous critical finding. A total of 140 findings were reported:
· 5 Critical findings:
- 2 Related to risk management
- 2 For ongoing safety evaluation
- 1 For the management of adverse drug reactions (ADRs)
· 59 Major findings:
- Majority of which were related to risk management and management of ADRs
- Other major findings were associated with ongoing safety evaluation and the quality management system (QMS)
· 76 Minor findings:
- Most common minor finding was for the QMS
- This was followed by risk management, ongoing safety evaluation and management of ADRs
· Four inspections had no reported findings
Regardless of grading, the most common finding (28%) was related to the QMS, followed by risk management (22%) and ongoing safety evaluation (21%). These three topics were also the most common findings in 2019/20.
Revised Inspection Model
Since 2019, the GPvP inspection programme has had four discrete inspection arms which inspections are conducted under. This inspection model allows the GPvP Inspectorate to assess specific PV activities against a set of objectives and evaluate specific technical topics within a scope. They can be summarised below:
· Routine pharmacovigilance activities:
- Objective: Assess whether the MAH has the ability to identify, characterise and report new or changed risks for their medicinal products.
- Collection and collation of safety data
- Management of ICSRs
- Periodic safety update reports (PSURs)
- Signal management by the MAH
· Routine risk management and safety communication:
- Objective: Assess whether important safety updates have been communicated to patients and healthcare professionals in the UK.
- Maintenance of reference safety information (RSI)
- Implementation of approved changed to product information
- Safety communication, including DHPCs and educational materials
· Additional risk minimisation measures (aRMMs):
- Objective: Assess whether aRMMs are implemented in accordance with the agreed risk management plan (RMP).
- Tailored to individual risk management systems
- aRMMMs can include controlled access programmes, controlled distribution systems and pregnancy prevention programmes
· Non-interventional post authorisation safety studies (NI-PASS):
- Objective: Assess whether NI-PASS are conducted in accordance with the approved study protocol and that safety data is collected and reported appropriately.
- Study-specific inspections with visits to UK investigator sites as necessary
In the 2020/21 reporting period, the majority of inspections (25 of 37) were in the routine pharmacovigilance activities arm, six were in routine risk management, five were in aRMMs and one was in NI-PASS.
Routine Pharmacovigilance Activities Arm
Under this arm, 15 inspections were routine inspections (non-triggered). The following findings were reported:
· 1 Critical finding:
- In the area of ongoing safety evaluation – signal management
- Fundamental weaknesses in the PV processes resulted in the delay of identifying and rectifying a specific safety issue with a product
- Numerous product quality complaints affecting patient safety were received but a signal was not raised. MAH did not consider taking any further actions based on aRMMs that were in place
- Data in software used to conduct signal detection activities was inaccurate
- Product technical complaints (PTCs) with associated AEs had not been entered into the safety database for years and not submitted to EudraVigilance. Also, the PTCs were not considered in routine signal detection
- The standard operating procedure (SOP) for signal detection lacked detail, leading to non-standardised processes in document review, analyses and decisions made relating to signals
· 33 Major findings:
- Most reported in the area of ongoing safety evaluation (11 findings)
· 44 Minor findings:
- Most common finding was associated with the QMS (17 findings)
As for triggered inspections, 10 were conducted under this arm. The following findings were reported:
· 1 Critical finding:
- In the management of ADRs – case processing activities
- Identified in a triggered inspection based on intelligence obtained by the GPvP Inspectorate
- The MAH failed to record all reports of ADRs and did not process or capture them in the safety database
- Safety reports were received in a mailbox as attachments with no means of prioritising serious cases or adverse events of special interest (AESI)
- There was a backlog of cases which were subsequently not considered in signal detection activities
- There was no evidence of follow-up of reporting fatalities, AESIs and SAEs. This was linked to a major finding of lack of detail in SOP of the follow-up process
· 12 Major findings:
- Most were reported in the management of ADRs
· 15 Minor findings:
- Similarly, were most reported in the management of ADRs
Routine Risk Minimisation Arm
All six inspections under this arm were triggered, five of which were due to intelligence obtained by the GPvP Inspectorate and one due was due to a previous critical finding. The following findings were identified:
· 3 Critical findings:
1. Risk management – maintenance of RSI:
- Outdated (patient information leaflets) PILs were packaged with the product
- The product information was not updated in time as the quality safety variation submissions were too poor to be accepted by the authority
- The SOP for the maintenance of product information had deficiencies
2. Risk management – implementation of aRMMs
- The MAH failed to implement aRMMs for several marketed products for years
- There were no documented procedures to describe the process of implementing aRMMs
3. Ongoing safety evaluation – periodic safety update reports
- The MAH failed to prepare and submit PSURs for two products
- Also failed to submit variations to the MHRA to implement the outcome of Periodic Safety Update Single Assessment (PSUSA) procedures for both products – these variations were particularly important as the PRAC recommendations included adding safety warnings in SmPCs and PILs for the products
· 10 Major findings:
- Most were reported in the area of risk management (6 findings)
· 10 Minor findings:
- Most were associated with risk management and the QMS
Additional Risk Minimisation Measures (aRMMs) Arm
Under this arm, one routine inspection was conducted which had no reported findings.
As for triggered inspections, four were conducted under this arm, three of which were triggered due to intelligence obtained by the GPvP Inspectorate. Findings were only reported in one of these inspections:
· 1 Major findings
· 2 Minor findings
These were related to the risk management subtopic of additional risk minimisation activities in Part V of the RMP.
Non-Interventional Post Authorisation Safety Studies (NI-PASS) Arm:
One inspection was conducted under this arm which was triggered due to acritical finding from a previous inspection. A total of six findings were reported:
· 3 Major findings:
- One related to additional PV activities in Part III of the RMP
- One reported under the management of ADRs as there were deficiencies with case processing activities
- One reported under the QMS, specifically related to audit of NI-PASS
· 3 Minor findings:
- One also related to additional PV activities in Part III of the RMP
- Two findings were reported under the QMS regarding PSMF management and documented procedures
The evolving GPvP inspection model
Over the years, the average number of major findings per inspection has decreased from the previous reporting period, 2019/20 (from 6 findings per inspection to 4). This could be due to the inspections being conducted with more targeted objectives and a reduced scope as a result of:
· changes in the GPvP inspection model as outlined above – more targeted approach to inspection activity focused on different aspects of the PV system.
· the COVID-19 pandemic – prioritising specific for cause inspections and high-risk routine inspections conducted in line with the priorities of the MHRA’s Vigilance and Risk Management of Medicines division and the regulatory flexibilities that were introduced in April 2020.
This new targeted and more efficient approach could also explain the significant increase in the number of inspections conducted (from 22 in the 2019/20 reporting period to 37) and the decrease in the mean number of days per inspection (from ~10 in 2019/20 to ~7) in the 2020/21 reporting period.
In the coming year, the GPvP Inspectorate will apply a revised risk-based methodology by performing separate risk assessments for each inspection arm. PV systems, products and non-interventional studies which are considered to be the highest risk will be prioritised for inspection.
1. Pharmacovigilance inspection metrics, 2009 to present - GOV.UK (www.gov.uk)
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