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.

Keynote

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:

  1. Patient/Public engagement: There is a need for patients and the public to be listened to, and be involved in the medicines development and approval process. The MHRA are in the process of implementing innovative ways to facilitate this.
  2. The changing political landscape (Brexit): It is important to keep in mind that the UK will stay aligned with EU law throughout the implementation period. The MHRA is continuing with its work to adapt its procedures following the outcome of the Brexit challenge. Therefore, if and when changes do happen, there will be consultations, published guidelines and updates to the Human Medicines Regulation, all of which will ensure that the MHRA continues to act in the best interest of patients and public health.
  3. PV knows no boundaries: There is a need for continued international collaboration, irrespective of the Brexit outcome, through Regulator Collaborations, engagement in the building of PV systems and methodologies in low and mid-income countries, and also, importantly, through innovation e.g. emerging technologies and artificial intelligence.

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.

Inspection Trends, Metrics and Case Studies

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:

  1. Transparency – improves and shows consistency
  2. Opportunity to reflect on practices (Regulators to provide clarity) – improves compliance and quality standards
  3. Metrics based on facts – no statements or judgements

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:

  1. Risk Management:
    - use of outdated Package Leaflets and Product Information (Reference Safety Information)
    - non-compliant/ineffective additional Risk Minimisation Measures
  2. Quality Management System
    - inability to appropriately manage and close out known non-compliance issues and/or Corrective Actions and Preventative Actions (CAPAs)
    - lack of adequate oversight for compliance management of key pharmacovigilance vendors
  3. Provision of incomplete and often contradictory data for inspections (highlighted as an emerging trend following a review of findings from previous years).

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.

A Glance into the Future

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:

  1. Maintain its risk-based inspection programmes focusing on the highest risk organisations, PV systems and products (this will include organisations with significant acquisitions and merges)
  2. Ensure adequate supervisory coverage of the risk-based inspections
    - there will be varied inspection approaches ranging from full PV system inspections to targeted PV processes and product-specific inspections
    - the mode of interaction will also be changing with some inspections performed remotely
    - initiation of a compliance management process for the management of known or suspected non-compliance (not considered an inspection by the MHRA)
  3. Continue to adapt and develop innovative ways to tackle the changing PV landscape through:
    - patient-centric strategies
    - machine learning and cognitive computing (AI) – GxP AI focus group created to look at ways of incorporating AI in Regulatory Science
  4. Continue to strengthen global partnerships with regulatory colleagues

Educational Information on the Management of Safety Data from Patient Support Programmes

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:

  1. They have a good oversight and understanding of all sources of safety information relevant to their PV programmes
  2. They have written procedures that adequately describe how data is collected from solicited and unsolicited sources – organised data collection tools should be specific
  3. They have implemented appropriate measures to collect and collate safety data arising from PAPs/PSPs (inspectors would likely perform source data verification to identify any likely AEs have been missed)
  4. They ensure all eligible reports have been sent to the appropriate Regulatory Authorities
    - Patient deaths through organised data collection should be followed up where possible
          - Outcome only reports are not valid (in the EU/UK) and reporting should not be expedited
          - Outcome only reports should always undergo expedited reporting to the FDA, unless a causal association is ruled out by the MAH/company

Closing Remarks

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:

  1. MHRA as a driver for future change and vision
    - focusing on scientific and technological advances, the need to increase transparency and a growing international role through key partnerships
  2. The 3S [Smart Safety Surveillance] program
    - MHRA’s role in the assessment of the geographical distribution of product launches and thus strengthening PV in low and middle income countries
  3. The application of the new PV strategy to incorporate one common vigilance platform through a vision for vigilance transformation (covering medicinal products as well as medical devices).

Mr Foy emphasised how these strategies further emphasise how the MHRA is working hard to protect and improve public health globally.