Globalizing the Pharmacovigilance System Master File: Challenges and Opportunities
Clare Lavery
AstraZeneca Limited
Joanne Emmott
Merck Sharpe & Dohme (UK) Limited
Sabine Jeck-Thole
Boehringer Ingelheim GmbH
Pascale Rouben
Bristol Myers Squibb International Corporation, Belgium
Clare Lavery
AstraZeneca Limited
Joanne Emmott
Merck Sharpe & Dohme (UK) Limited
Sabine Jeck-Thole
Boehringer Ingelheim GmbH
Pascale Rouben
Bristol Myers Squibb International Corporation, Belgium
Dionne Usher
Merck Sharpe & Dohme (UK) Limited
Willemijn van der Spuij
Bristol Myers Squibb SA, Switzerland
Louise Woodward
Roche Products Ltd, UK
T

he requirement for a Pharmacovigilance System Master File (PSMF) was introduced in the European Union (EU) legislation in 2010. The PSMF provides the description of the European Marketing Authorisation Holder’s pharmacovigilance (PV) system, and according to the legislation, supports their compliance with the legislative requirements, e.g., by fulfilment of QPPV supervision and verification by national regulatory agencies (NRA). The Implementing Regulation, and in 2012 the EU Good Pharmacovigilance Practices (GVP) Module II guidance, provides a framework allowing a flexible accommodation of the different organizational structures of marketing authorization holders (MAHs). Since 2012, the concept of the PSMF has evolved in countries/territories outside of the EU, creating challenges for industry related to maintenance and production.

This article provides insights from the PSMF Networking Group (PSMF NG), an informal industry expert working group, on the potential considerations and opportunities for a global approach to the PSMF, driving easier maintenance and production. Awareness and continued dialogue are imperative.

The Arab League, Eurasia, East Africa, and most recently China are just a few examples of territories where the PSMF concept has evolved since 2012. The various requirements for a PSMF, or in some territories an equivalent document, appear to reflect the EU principles of the PV system description, to reflect the mechanisms for oversight and facilitate audit planning. A concept for success, surely! However, the challenges of managing local/regional requirements, such as country-specific details, organization charts, metrics, and lists of approved products in specific formats, prove to be complicated and burdensome in practice. The varying regulations lead to logistical challenges for MAHs, and global alignment and clarity on expectations from NRAs are needed. Coverage of this topic in the literature, especially regarding practical implementation of the PSMF, is limited. In summary, the production and maintenance of the PSMF is a manual and administrative task and process. The authors, the PSMF NG, favor standardization of requirements and PSMF compilation to benefit data quality in the PSMF.

The Global Challenge

It is the experience of the PSMF NG that producing PSMFs (or equivalent documents) to meet the different legislative requirements and various inspectorate expectations across the globe raises challenges for industry, in particular, to ensure consistency and scale up production while maintaining quality. For companies that have developed systems or programs to enable standardized and quick retrieval of data addressing country-specific needs, the task may be more easily manageable. However, in many cases, this may be a manual task and therefore prone to errors. In addition, it poses a significant administrative and resource burden.

Taking on the Challenge

The PSMF NG has met regularly since 2017 to analyze the regulatory landscape, to exchange on the implementation of the new and emerging PSMF regulations, to check the mutual understanding of NRAs’ expectations, and to consult respective publications. The PSMF NG has observed a variability in how MAHs maintain the PSMF, partly triggered by the differing assessment of the heterogenous guidance and their implementation status, the structure as well as the portfolios of the company they work for. Despite the divergent operational aspects, the PSMF NG has made the following important observations:

  • Companies are using their EU PSMF as a repository for their global PV system information and adapt the EU PSMF process and documents to meet requirements in ex-European territories.
  • There is an administrative burden of maintaining multiple PSMFs in multiple jurisdictions, essentially containing the same information but with local variations.
  • Thoughts for standardization appear to be similar across companies, highlighting a desire for alignment of requirements across NRAs and a true global approach.
  • And there is a common wish that NRAs only request a company’s full PSMF with its thousands of pages as part of an inspection preparation, and not as part of a marketing authorization application (MAA). Companies have leaner ways to confirm that they do have a compliant PV system in place in support of MAAs and/or renewal applications.

The MAHs’ commitment to operationalize and provide the PSMF in compliance with all applicable regulatory requirements and NRA expectations is clear and unprecedented. They acknowledge the PSMF as an essential, central point for access to key PV data, enabling oversight of PV system organization and performance for relevant stakeholders within the MAH (PV Auditors, QPPVs/locally responsible PV persons) and externally, namely NRAs (including their inspectorates). The PSMF NG has observed that a high-quality PSMF helps to drive PV inspection focus, may save time on-site, and provides PV Inspectors and key internal stakeholders with accurate information that can be consistently obtained.

Sharing their experience, the PSMF NG wants to create awareness of the practical implications and challenges for industry since the PSMF has gone global. Opening up the discussion between all impacted stakeholders such as regulators (including inspectorates) and industry (auditors, QPPVs and PSMF Coordinators and Contributors) may undo the Gordian knot, leading to harmonization of requirements, simplification of maintenance needs, and a reduction in duplicated efforts and administrative impact.

Our Wish: Simplification and Harmonization

Simplified maintenance is needed as well as a pragmatic, harmonized approach to ensure that a company’s PV system at both the global and regional/local levels is appropriately presented in the PSMF in a format that is acceptable to all NRAs across the globe. The format should be modular and available in local languages, if required. For example:

  • A global “main body” document that allows easy navigation and provides:
    • details of the regional/local QPPV, as applicable; and
    • a single description of a company’s global PV system that can be utilized in any territory and is available upon request for inspection and oversight purposes.
  • Global annexes that provide the operational and compliance details of the PV system.
  • Relevant local/regional annexes also available upon request for inspection and oversight purposes.
  • A harmonized template for a “Summary of the PV System,” signed by the relevant/local QPPV and an authorized local representative of the company and submitted for regulatory purposes, such as filing to obtain a marketing or a license renewal, with the trust that companies can provide a full-text PSMF to the NRA within a very narrow timeline (e.g., seven calendar days).

To Conclude

Discussions within the PSMF NG have reflected on the value of the PSMF but also served to highlight a need to raise awareness of the practical challenges experienced by industry arising from the globalization of the PSMF. Dialogue between industry and NRAs (for example through inspections, as well as conference platforms such as DIA) is extremely valuable. The PSMF NG would welcome continuation of this dialogue with respect to globalization of PSMF requirements, including their simplification and harmonization.

Please direct all correspondence to Clare Lavery, AstraZeneca Limited, Silk Road Business Park, Charter Way, Macclesfield, Cheshire, SK10 2NA, England. Clare.Lavery@Astrazeneca.com.