The Pharmacovigilance System Master File
Derek Woodcock gives an overview of the Pharmacovigilance System Master File in our safety and pharmacovigilance themed month.
The requirement for a Pharmacovigilance System Master File (PSMF) has been in place since July 2012 for all Centrally Approved Products or at the time of the application or renewal for Nationally Approved Products (or by 21 July 2015, whichever is earliest). This means that Marketing Authorisation Holders (MAHs) and Competent Authorities now have an amount of experience, not just in terms of their set up, registration and maintenance, but also in terms of their usefulness and whether or not they have delivered the resource efficiencies that they initially promised.
Prior to the PSMF there were the detailed Description of the Pharmacovigilance System (DDPS) that was submitted with each new application (as Module 1.8.1) and the Summary of Pharmacovigilance System (SPS) that was submitted at the time of an inspection. A single PSMF that is linked to all MAs falling under one pharmacovigilance system can now serve to meet both functions; a summary (e.g. in an Annex of the PSMF) can fulfil the requirements of 1.8.1, there is no need for multiple variations when there changes the PV system, and the PSMF (when active) is submitted instead of the SPS. A system-focus is particularly relevant for generic manufacturers and given that the new pharmacovigilance legislation enables the EMA to charge fees for its new pharmacovigilance activities, a single PSMF is a proposed justification for a rationalised pharmacovigilance fee1.
In April this year we had the first revision to the Guideline (GVP Module II); the revision clarified the requirements for a PSMF for applicants for, and holders of, registrations of traditional herbal medicinal or homeopathic products.
In addition to the Module itself, there are several good official resources that answer many questions on the PSMF, and should be referred to for format, submission and maintenance:-
• EMA
• MHRA
"In April this year we had the first revision to the Guideline..."
Where there is a GVP Module, there is also a potential source of inspection findings. Allowing time for companies to get up and running with their PSMFs, the inspections have been against the new regulations for only a few months now. Even so, we have seen a selection of findings that have been given by MHRA2;
• Insufficient detail in the primary topic sections
• Non-comprehensive details of sources of safety data (e.g. details from non-EU sources, studies and Patient Support Programmes are missing)
• Inadequate description of approach to plan audits
• No documented link between audit findings and CAPAs
• Inadequate description of system performance monitoring (e.g. in relation to quality of ICSRs and timeliness of safety variations)
• Non-comprehensive list of contractual arrangements (e.g. agreements between overseas partners and third parties, even though these are not direct agreements with the MAH)
• Missing compliance data (e.g. ICSR/PSUR submissions in different regions).
Surprisingly, and resulting in a "major" finding, are instances where a MAH has submitted an application referencing a PSMF – but at inspection there is no evidence of a finalised (live) version!
Is the PSMF simply a source for more "findings" or a useful tool? Prior to its introduction, it was described as a means of strengthening of supervision – not only by Competent Authorities, but also within MAHs.
Benefit for QPPV and MAH management
Managerial staff in any organisation should be responsible for reviewing the pharmacovigilance system including its quality system at regular intervals in risk-based manner to verify its effectiveness and introducing corrective and preventive measures where necessary3 – in other words a frequent "health-check" of the system.
To serve its purpose the PSMF must be supported by senior management and have cross-functional input, in particular from Quality and maintained up-to-date. Module II lists the types of changes that should be routinely and promptly notified to the QPPV, but in practice the PV team will need any and all changes that affect its content, including (but not limited to):
• New or reissued contracts (e.g. with commercial distribution partners) or SOPs concerning PV-related services.
• Changes in corporate structure or organisation ownership
• New (or withdrawn) marketing authorisations
• Results from audits (and deviations) concerning pharmacovigilance
• Changes in arrangements for the provision of the pharmacovigilance system master file to competent authorities.
Whilst the recipient QPPV should explicitly see changes listed in Module II (and explicitly accept transfer of responsibility to a QPPV) the QPPV should regularly check the Log Book for a record of all other changes made to file's main body. This supports the authority of the support staff maintaining the file and provides an opportunity for the QPPV to positively demonstrate oversight. As a contractor QPPV, the fact that this requirement is very clear to my client MAHs is of help.
The QPPV oversight of compliance (e.g. in respect of timeliness of submission of regulatory reports) is facilitated by reference to the relevant Annex in the PSMF. Whist the implementing directive states that a list of performance indicators may be included the GVP Module states that they must be provided. The EMA may yet publish a list of performance indicators on the basis of a recommendation of the Pharmacovigilance Risk Assessment Committee, and we are currently assuming these will be the same as the performance metrics produced by MAH. There is an argument that these should be made available 'on request' (rather than continuously updated in the PSMF), but equally a contractor QPPV may find the PSMF a suitable place for regular updates.
"...there are several good official resources that answer many questions on the PSMF..."
Benefit for competent authorities
In addition to harmonisation of presentation and simplification of procedures above (e.g. during inspection), the PSMF is used to help assessment of new Marketing Authorisation applications and at renewal. In addition to the overview, a critical assessment of the impact of findings from pharmacovigilance inspections on the benefit/risk balance of the medicinal product as provided by the MAH should be discussed in the Assessment Report. This will extend to assessment of audit findings in the PSMF. There has been some misunderstanding (now clarified) concerning the sentence, "the audit report must be documented within the quality system"; it does not mean that the reports themselves need to be included in the PSMF. However, a brief description of the corrective and/or preventative action(s) associated with any significant findings (within the classification of "critical" or "major"), cross-referenced to the report, must be included in the body of the PSMF.
Conclusions
The primary benefit of the PSMF concept over the DDPS is the reduction in burdensome and duplicative work practices. However, the PSMF itself has created considerable extra work for many and some of the initial findings from inspection (e.g. some areas containing "insufficient detail") may suggest that the balance – between overview information on the key elements of the system rather than a depository for the primary data relating to individual elements – has yet to be achieved.
References
1. European Generic Medicines Association (EGA): Comments on the Concept Paper on the Introduction of Fees to be charged by the EMA for Pharmacovigilance. http://ec.europa.eu/health/files/pharmacovigilance/2011-11_phv_fees_pc/26_ega_en.pdf
2. GVP Symposium 2013, MHRA
3. GVP Module I – Pharmacovigilance Systems and their Quality Systems
About the author:
Derek Woodcock is in independent consultant at CrossOak Pharma Ltd providing pharmacovigilance consultancy services and is a contractor EEA QPPV and PV auditor. A registered pharmacist with over 30 years experience in drug safety, regulatory affairs, medical information and product development, Derek previously held the post of Chief Scientific Officer for Britannia Pharmaceuticals Ltd.
The new pharmacovigilance legislation has created increased demand for independent auditors and help with integrating pharmacovigilance into Quality Management Systems. This has given Derek the opportunity to advise a number of companies with their PSMF and its management.
Is the PSMF simply a source for more "findings" or a useful tool?
