What is a Pharmacovigilance Agreement?
A pharmacovigilance agreement (PVA) is a written agreement between the marketing authorisation holder (MAH) and a third party (to which the MAH has shared or activities regarding or impacting pharmacovigilance), which outlines the responsibilities of each party with regards to pharmacovigilance.
Within the European Union (EU), much of the guidance of what should be included in a PVA is detailed in Good Vigilance Practice (GVP) Module I1. The module explains that although it is acceptable for the MAH to certain pharmacovigilance activities to a third party, the MAH retains full responsibility for the compliance of these activities and must ensure there are mechanisms in place so that the qualified person for pharmacovigilance (QPPV) can access all relevant information from these sources. The ultimate responsibility of the MAH is one of the reasons for the importance of a thorough PVA, to ensure full oversight of activities.
Common reasons for PVAs are:
GVP Module I1 makes it clear that the subcontracts should be detailed and clearly describe the arrangements for delegation and responsibilities of each party, to enable each party to be compliant with legal requirements (whilst not specifying precisely what should be included in the PVA). The themes outlined in Module I provide a skeleton for what should be included in a PVA, however it also gives the scope for MAHs to cover additional topics, should they consider it necessary. From the GVP guidance, it is clear that a PVA is now much more than a document that only covers the exchange of cases, which was routine practice not long ago. The industry has welcomed the indefinite nature of the guidance in this area, which has contributed to the PVA becoming an all-encompassing document, as MAHs develop PVAs to suit their individual needs.
Important aspects of Pharmacovigilance Agreements:
The scope is key to set the scene for the rest of the agreement. Within the scope, both the products and territories covered by the PVA (and by which party) can be defined. However, it can be more straightforward to have this information detailed in an appendix to the agreement if the products/ territories covered are extensive and subject to frequent change. Another area which could be included in the scope, is to define the role of each party. An example might be confirming which party is the MAH and which is the distributor? Are the parties both MAHs but in different territories? Or perhaps, is the distributor also the local MAH? This information will aid the understanding of the reader when considering the requirements of each party. Another item for inclusion within this section could also be the language that information should be exchanged in. This is an important point, as the partner companies might have offices in countries that speak different languages. Therefore a common language needs to be selected. The party that will transmit the information to the regulators and the language enforced by the regulators in a territory should also be considered.
2) Exchange of Cases
As per GVP Module I1; collecting, processing and managing individual case safety reports (ICSRs) is a critical pharmacovigilance process. It is essential therefore, for this to be included in the PVA. Within this section, there are vital areas which need to be covered. Firstly, the type of cases collected by each partner needs to be defined (e.g. post-marketing, clinical studies, registries, market research), as well as whether both serious and non-serious cases are required to be exchanged. Similarly, it is necessary to define which party is responsible in which territory. Equally, special situations, and the expectations for collecting cases associated with these instances, should be clearly defined. All of the above is important to ensure no sources of safety data are missed and conversely that there is not a duplication of case submissions. The format in which cases are exchanged also needs to be specified. This is important to ensure that the format is compatible with what the global PV database holder requires for import and submission of cases. Another crucial component is to define the timeline for exchange of cases, including a definition of day zero to ensure there is no misunderstanding between partners. Indeed, GVP Module VI2 states “The clock start for the submission of ICSRs begins with awareness of the minimum information by either the organisation or the contractual partner (whichever is the earliest).” This being defined in the PVA, along with how many working or calendar days the partner has to forward the cases to the MAH, ought to minimise late submission of cases to regulatory authorities. Including this case exchange information, should ensure that each company will receive the reports it needs to meet regulatory authority requirements.
3) Aggregate Reports
As per GVP Module I1; scheduling, preparing and submitting periodic safety update reports (PSURs) is another critical pharmacovigilance process. Similarly, development safety update reports (DSURs) are vital to pharmacovigilance within clinical trials. Therefore, this is another important aspect of any PVA. One reason for this, is the requirement to submit aggregate reports to the regulatory authorities within certain timeframes. If this requirement is consistently not met, an inspection could be triggered. Additionally, aggregate reports are thoroughly assessed by the authorities and a lack of safety data from partners could be detected, triggering a subsequent authority inspection. As part of the PVA section for aggregate reports, the responsibilities for the preparation of the report must be defined; who will write the report, what are the responsibilities of the supporting party (for example, provision of sales data). This is important to ensure the report represents the global availability of safety data. Furthermore, the reviewers and timelines for review should be defined, as well as who will approve the report. Defining all of this in the PVA, prior to report preparation, should ensure that the process occurs smoothly (without duplication of effort) and that there is sufficient time for each party to review and input into the report prior to submission. Finally, the party responsible for submission (and prior electronic common technical document (eCTD) formatting if required) should be defined. Careful documentation of these timelines, will ensure timely reporting to the regulatory authorities. If there are any territories included in the agreement which are outside of the EU, reporting and requirements in these territories should also be considered. Choosing the most appropriate party to handle this (perhaps the party with presence in the non-EU territory) is important to ensure any local requirements are met.
4) Product Information
Communicating changes in risk:benefit to healthcare professionals (HCPs) and patients is another key process in pharmacovigilance1. Awareness of the risks associated with products is fundamental to patient safety. One way that this is accomplished, is through providing up to date product information (summary of product characteristics (SmPC), patient leaflet (PL) and packaging). Furthermore, and according to the United Kingdom’s Medicines and Healthcare Products Regulatory Agency (MHRA) Pharmacovigilance Inspection Metrics Report (April 2016 – March 2017)3, major findings in relation to the maintenance of reference safety information increased significantly in the reporting period. Within this section of the PVA, it should be specified whether there will be a company core data sheet, and who will maintain it, along with who will be responsible for updating local SmPCs. Another important aspect is to confirm who will be responsible for communicating with the regulatory authorities and how the updates will be shared (both within the partner companies and with the public/ HCPs). If the above is not sufficiently defined, then even if the updates were completed, the information might not reach patients and HCPs in all territories where the product is marketed. In addition, if the update is driven by the regulatory authority contacting one of the parties, timelines for notifying the other party should be defined, as well as a clause to manage any disputes regarding the response to the regulatory authority. It is useful to define this in order that the most appropriate party (i.e. the MAH or the company with presence in the local territory where the authority request has been made) can communicate with the authority effectively.
5) Audits and Inspections
GVP Module I1 states that contracts with partners “should indicate which processes are in place for checking whether the agreed arrangements are being adhered to on an ongoing basis. In this respect, regular risk-based audits of the other organisation by the MAH or introduction of other methods of control and assessment are recommended.” Therefore, a section which gives the right for each party to audit each other in respect of the activities described in the PVA, is completely essential to ensure that all aspects of the PVA are being adhered to and the legal obligations of each party are being met. An important feature of this section is that the responsibilities of any remedial actions should also be defined. This is important as, without this, following audit findings, corrective and preventative actions may not be put in place and the PVA may continue to be disregarded. With respect to inspections, it is important for the PVA to state that each party should notify each other if they are to be inspected (and within what timeframe). The PVA should also state that the other party will provide necessary support and requested documentation, during the inspection. This is imperative to ensure cooperation at the time of inspection and demonstrate that the PVA is effective. This will reassure the inspector that there is optimal product safety risk management.
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- Guideline on good pharmacovigilance practices (GVP) – Module I – Pharmacovigilance systems and their quality systems (Rev 1). EMA/541760/2011. European Medicines Agency; 2012. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129132.pdf (Date Accessed: 06/01/2018)
- Guideline on good pharmacovigilance practices (GVP) – Module VI – Management and reporting of adverse reactions to medicinal products (Rev 1). EMA/873138/2011 Rev 2. European Medicines Agency; 2017. Available from URL: http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2017/08/WC500232767.pdf (Date Accessed: 06/01/2018)
- Medicines and Healthcare Products Regulatory Agency (MHRA). Pharmacovigilance Inspection Metrics Report (April 2016 – March 2017) [Internet]. London. 2017. Available from: https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/664019/Pharmacovigilance_Inspection_Metrics_Report_2016-2017_Final.pdf (Date Accessed: 06/01/2018)