This article covers some important highlights from the MHRA Good Pharmacovigilance Practise (GPVP) Symposium held in London on 11 February 2020. The symposium provided a mixture of inspector-specific insights through the presentation of trends and metrics from inspection findings, and some educational/informative sessions comprising panel discussions, inspector surgeries and the cross-agency (US-FDA + MHRA) presentation on the approach to Patient Assistance and Patient Support Programmes (PAPs/PSPs). The closing remarks provided a window to view the MHRA’s future plans and how innovative ideas are being put in place to support Regulatory Science in the UK and globally.
The renowned Dr June Raine, Interim Chief Executive, MHRA and formerly Chair of the European Medicines Agency Pharmacovigilance Risk Assessment Committee, delivered a succinct, yet stimulating keynote speech to kick off the event; encouraging delegates to “get bang up to date”, and take advantage of the opportunities to engage and forge relationships. In her early statements, she reminded delegates that the aim of pharmacovigilance (PV) is to promote and protect public health and that “a high standard operation of PV underpins confidence and trust in medicines”.
The top challenges faced by the MHRA were highlighted:
Dr Raine closed her speech by commending the efforts of the MHRA staff, and noted that there was an added emphasis on the improvement of systems (within the MHRA and across multiple stakeholders and collaborators) to establish future efficiencies in the three key areas of Safety, Collaborations and Compliance. Delegates were urged to challenge current thinking, interact and collaborate with inspectors and other stakeholders, and proactively share knowledge and best practices.
The MHRA GPVP inspectorate provided some key inspection metrics, trends, hot topics and case studies (focusing on some prevalent critical findings) from inspections carried out within the fiscal year April 2018 to March 2019. The need to report inspection metrics as laid out within the Hampton Report of March 2005, covers (with regard to the MHRA), the following areas:
The GPVP Inspectorate stated its intention to improve “expected” compliance through education and understanding of requirements and improvement of systems. Since inspections are carried out using a risk-based approach, the focus is on products, organisations and systems that are “high-risk”, in order to ensure and maintain adequate public protection.
In the period April 2018 to March 2019, a total of 18 Marketing Authorisation Holders (MAHs) were inspected by the MHRA GPVP Inspectorate. The average number of findings per inspection was consistent with that of previous years (6-7 findings). There were 4 critical findings, 78 major findings and 38 minor findings within this period. The critical inspection findings within this period included:
These critical findings were from inspections on high-risk product/systems for which 15 of the 18 MAHs were innovative pharma companies and almost half were new MAHs [<5 years MAH status]. They clearly show that non-compliance in any area of PV has the potential to adversely affect the rights, safety and quality of life of patients and the general public.
In a summary analysis of the major findings, it was noted that (i) Risk Management (again); and (ii) Management of ongoing safety evaluations, are the areas in which major findings are most prevalent. Non-compliance in the provision of information for supervision by competent authorities (often incomplete and/or contradictory information) is also emerging as an area of major findings.
With respect to critical findings, the GPVP inspectorate used 3 case studies to highlight issues and pitfalls that would have a bearing on the outcome of any re-inspections. The case studies highlighted that an important key to a successful resolution of any issues is to “Begin with the End in Mind” (understand the main aim and put measures/plans in place, and work diligently to achieve them). The inspectors stressed that it is not adequate to attribute “human error” as a root cause – it is more appropriate for organisations to focus on the procedural issues and ensure that strong processes are in place to mitigate such errors.
In the same vein, it was emphasised that it is not sufficient to just perform an adequate Root Cause Analysis only. MAHs are also required to demonstrably show that they have (i) completed a Full Impact Assessment (further evaluation) to establish the extent of the issue; (ii) designed, assigned and initiated appropriate CAPAs; (iii) demonstrated good governance or oversight management, tracking and review (deliverables) of any actions; and (iv) establish appropriate timelines (due dates) to ensure any issues or findings are adequately addressed, and that there is oversight of progress until full resolution of the issues.
It was illuminating to learn from the inspectors’ perspective in these case studies. On a personal note, I developed a deeper appreciation of the amount of effort involved in helping companies and individuals achieve and maintain compliance and, I was interested to note that there has been a steady and gradual shift in the management of identified compliance issues from a “restrictive approach” (e.g. products withdrawn) to a “managed-risk approach” in which measures are put in place to ensure the safe and effective use of medicines, so that withdrawals only happen in the worst cases when gross non-compliance has been detected.
With respect to Brexit (UK’s withdrawal from the EU), it is currently difficult to state, with any certainty, what the MHRA’s involvement with the EU will be at the end of the transition period. It is important to note however that, for Centrally Authorised Products, the QPPV and PSMF can continue to be located in the UK during the transition period and the MHRA will continue to operate as the Supervisory Authority for MAHs when the PSMF is located in the UK. Conversely, pending the announcement of future requirements, the requirement for a UK based QPPV and PSMF will become effective 21 months after the end of the transition period.
There is also continued access to EU inspection reports and risk information as well as ongoing sharing of MHRA inspection outcomes during the transition period. Discussions are ongoing with the aim of ensuring that the MHRA continues to be aligned with the EU for the purpose of medicines and health products regulatory activities beyond the transition period. However, should this not materialise and there is ‘no-deal’ and no extension to the transition period, the MHRA has vowed to continue working in the best interest of patients. As and when more information becomes available, guidance documents, blogs and amendments to UK laws will be published and implemented to aid industry and the public. Irrespective of its continued involvement in the EU, the MHRA will:
There was an insightful cross-agency (MHRA and FDA) presentation on the approach to Patient Assistance and Support Programmes (PAPs/PSPs). Whilst the definition of PAPs/PSPs may differ slightly between the two agencies, there is a consistent theme on how safety data generated from these sources are to be managed. The speakers noted that there is a pending update to the existing ICH E2D (Post-approval safety data management) guideline which will clarify the management of post-approval safety information from new and increasingly used data sources.
Any organised form of data collection in which the MAH/company “reaches out to” the reporter via a planned contact must be considered ‘solicited’. “Solicited” reports of adverse events (ADEs), must undergo a causality assessment to consider whether they meet the definition of a suspected ADR and, thus, meet the minimum validation requirements for expedited reporting. In the EU/UK, expectedness is not a factor in the requirement for expedited reporting but, US FDA reports also require the MAH/company to assess whether there is at least a reasonable possibility that the drug caused the adverse drug experience (ADE); the report would only meet the expedited reporting criteria if it is also considered to be unexpected. MAHs/companies are urged to implement systems to collect AE reports and also monitor the compliance of these systems.
In contrast, incidental reporting in which the reporter initiates the communication (in an unsolicited manner) without a prior planned interaction, must be considered ‘spontaneous’. There is no organised data collection in this scenario and, as such, causality is always implied.
It is important to correctly categorise, and set-up appropriate measures to collect and collate all AEs from both solicited and unsolicited sources. Appropriate contractual language, training of staff and 3rd parties on the use of data collection tools, periodic or one-off reconciliations, and quality assurance activities have a strong legal remit in the EU/UK.
From the MHRA Inspectorate perspective, there is a need for MAHs to satisfactorily demonstrate that:
Mick Foy’s closing remarks were somewhat reminiscent of the keynote speech from Dr June Raine. He touched on the following three aspects of the MHRA’s PV strategies:
Mr Foy emphasised how these strategies further emphasise how the MHRA is working hard to protect and improve public health globally.