The concept of the Pharmacovigilance System Master File (PSMF) was first introduced in European Union (EU) legislation in 2010 [1, 2] with the Commission Implementing Regulation No. 520/2012 [3] and GVP Module II [4] providing requirements and guidance, respectively, in 2012 for EU Marketing Authorisation Holders (MAHs) on the operational aspects of the legislation. The PSMF replaced the earlier requirement for a Detailed Description of the Pharmacovigilance System (DDPS) [5].

Since the introduction of the PSMF in the EU, national regulatory authorities (NRAs) in other territories have introduced similar legislation and/or local Good Pharmacovigilance (GVP) guidelines that include PSMF requirements (see Section 1.1.2. Other Territories).

Whilst it is recognised that the PSMF has multiple benefits (e.g., internal/external oversight of the pharmacovigilance [PV] system, a central place for PV information, internal training purposes), pharmaceutical companies have experienced practical challenges in maintenance and implementation due to the varying requirements, their different interpretation and lack of global legislative harmonisation.

To discuss the topic of managing the PSMF in the evolving PV landscape and to exchange best practices, the authors (members of the PSMF Networking Group,Footnote 1 hereafter referred to as the PSMF NG) have met regularly since 2017 to evaluate and discuss the implementation of global PSMF requirements, new and developing regulations and to check the mutual understanding of NRAs’ expectations. They conducted an industry survey in 2019 to better understand benefits and challenges, in particular when facing the globalisation of PSMF legislation. The results of this survey are reflected and evaluated in this paper, which

summarises the findings of the survey and the PSMF NG experience with regard to the construction and use of the PSMF globally;

aims to create awareness amongst stakeholders of the practical challenges for industry in addressing the global requirements;

aims to open up discussion with all stakeholders including NRAs and share future considerations to drive towards a global PSMF concept through harmonisation, simplification and reduced duplication of effort.

Global Pharmacovigilance System Master File (PSMF) Legislation and RequirementsThe European Union (EU)

The PSMF provides an overview of a company’s global PV system to contribute to the EU Qualified Person for Pharmacovigilance’s (QPPV) oversight and to the planning and conduct of internal PV audits. It is registered in the Extended EudraVigilance Medicinal Product Dictionary (XEVMPD) and provided upon request to support PV inspections by NRAs. The PSMF “should reflect global availability of safety information for medicinal products authorised in the EU, presenting information on the pharmacovigilance system applied at global, regional and local levels” [4]. Key aspects relating to the PSMF content are provided in Table 1 [4].

Table 1 EU Pharmacovigilance System Master File (PSMF): overview of current requirements

The Implementing Regulation [3] and EU GVP Module II [4] provide a framework that allows flexibility to accommodate the different organisational structures of MAHs. However, the experience of the PSMF NG is of differing interpretations by EU NRAs on the scope of the PV system and information to be presented in the PSMF; for example, requests for study data or vendor presentation may vary, wet ink signature requirements for PSMF-related documents, and NRAs may request a supplementary, ‘local’ version of the PSMF.

One of the intended objectives for the PSMF, outlined in EU GVP Module II, was to reflect the PV system in place and act as an oversight tool for the EU QPPV and NRAs. The experience of the PSMF NG is that through the evolution of MAH PV and quality systems in the time since 2012, including enhanced processes and mechanisms to assess and share feedback on system performance, there may now be additional ways in which oversight is provided to the EU QPPV/MAH Senior Management (e.g., participation in regular PV governance/compliance forums). However, the PSMF has undoubtedly contributed to improvements in oversight over MAH's PV and quality systems. It continues to serve as a tool that offers systematic and holistic oversight of the PV and quality systems and their performance, and enables greater connectivity with other departments contributing to the PV system, thereby indirectly raising the profile of PV and PV compliance within companies.

Other Territories

The PSMF concept continues to evolve in other territories with the introduction of requirements and/or expectations for a PSMF or equivalent document; examples include Arab League, Eurasia and India [6,7,8]. Requirements for a PSMF in the different countries follow the principles of oversight, PV system reflection and audit planning as introduced in the EU, but they also frequently focus on country-specific information (e.g., inclusion of country organisational charts, country-specific lists for approved products, studies and local PV service providers).

The PV regulatory landscape also continues to develop at different rates across territories. In some regions the requirements may be driven by well-established PV departments of a ‘lead’ NRA with other countries in that region just starting their development of a PV infrastructure, as described by Alshammari et al. [9]. Even where requirements have been set at a regional level, individual NRAs within the region may insist on additional documentation such as country-specific annexes, supplementary documentation, or translations in local language.

The aim of this paper is not to provide a detailed overview of the requirements in these territories. However, the PSMF NG’s collective experience of documents provided to comply with regulatory requirements are summarised in Table 2.

Table 2 Other territories: authors’ experience of Pharmacovigilance System Master File (PSMF)-type documents required by local legislation

From an industry perspective, an additional complexity is related to the varying document submission requirements across the countries/regions. These may include a PSMF kept on file and submitted only on NRA request, or submitted as part of a regulatory dossier (e.g., marketing authorisation application [MAA], renewal), or submitted after a major PV system change, or submitted annually, and/or a combination of any of these scenarios. It has also been noted that regulatory requirements in certain regions appear to be aligned with previous versions of EU GVP Module II, for example the Eurasian Economic Region and Arabic GVP Modules. The authors also note that, after the completion of the survey, further UK-specific requirements came into force in 2021 [10].

Summary

Both in and outside of the EU, it appears PSMF requirements vary because of interpretation, implementation status or actual country/regional requirements. Multinational companies are challenged with the task of complying with these requirements and interpretations. Manual adaptation and customisation of data reflected in the PSMF to address the requirements/interpretations are challenging, time consuming and duplicative and require quality control steps to ensure the delivery of high-quality data. Harmonisation and simplification have the potential to reduce the burden of PSMF maintenance and to create efficiencies in the process and therefore support and facilitate high-quality outputs.