To ensure a smooth transition from the pre-authorisation to the post-authorisation phase of the life-cycle of a medicinal product, it is the responsibility of the Marketing Authorisation (MA) applicant to have in place a robust Pharmacovigilance (PV) system for monitoring patient safety once the product is on the market. During clinical trials, patient exposure is limited and closely monitored, and there are very specific criteria for patients who are eligible to take part in the study. However, once the product is on the market and more widely available, patient exposure is much more widespread and patients may experience adverse reactions (ARs) that have not been observed previously in a clinical trial setting.
To maintain compliance with EU post-marketing regulatory requirements, the MA Holder (MAH) must ensure that the following are in place:
- PV systems (including appropriate technology, quality management system and PV processes)
- Qualified Person for Pharmacovigilance (QPPV) and deputy and local safety responsible representatives (where required under national legislation)
- Pharmacovigilance System Master File (PSMF)
- Risk management and minimisation systems
- Signal Management
- Global literature search strategy
- EudraVigilance (EV) maintenance including Article 57 database
A Pharmacovigilance systems must be in place to ensure the collection and management of suspected ARs, including non-serious ARs and ‘special situation’ events (e.g. off-label use, misuse and abuse, medication errors etc.). This information must be collated from all sources including spontaneous reporting from patients and healthcare professionals (HCPs), global literature, contractual partners, post-marketing studies and other solicited data collection activities and company managed social media.
For what concerns the Pharmacovigilance in the European Union (EU), there are centralised requirements for reporting ICSRs on an expedited basis including non-serious ICSRs occurring in the EEA to the EMA’s EudraVigilance database. Furthermore, generally for new products authorised in more than one EEA country, there are requirements to submit the Periodic Safety Update Report (PSUR) via a centralised repository for single assessment by the designated member state for the substance. The requirements to submit PSURs, including data lock points and frequency, are governed by the European Union Reference Date (EURD) list.
A common inspection finding is that the MAH has inadequate systems in place to collect/exchange safety information from internal departments (e.g. commercial and marketing department activities with market research and social media) and external parties (e.g. vendors and contractual partners where there is lack of oversight and/or deficient arrangements for safety data exchange in place). Additionally, there must be adequately resourced and qualified pharmacovigilance personnel, validated IT systems, comprehensive processes and a robust Quality Management System (QMS) in place.
For all products authorised within the European Union, it is necessary to have in place a Qualified Person for Pharmacovigilance (QPPV). The role of the QPPV is to oversee the entire Pharmacovigilance system and take overall responsibility for ensuring the integrity of the PV systems and patient safety data. The QPPV must reside in the European Economic Area (EEA), ideally in the same country as where the global safety database is held or main PV activities are conducted. It is important to note that there are equivalent requirements in certain non-EU countries for local safety responsible representation. Furthermore, some countries within the European Union require a local person resident in that country and/or fluent in the local language where this role is not assumed directly by the QPPV.
The PSMF is a “detailed description of the pharmacovigilance system used by the Marketing Authorisation Holder with respect to one or more authorised medicinal products” (Article 1 28 (e) Directive 2001/83/EC). It must be located within the EEA, preferably in the same location that the main PV activities are conducted or where the QPPV resides. It is a living document that is maintained in real time in accordance with the life-cycle of the product(s) and must be accessible and available upon request to the European Medicines Agency (EMA) and national competent authorities within the EEA.
Risk Management and Minimisation Systems
All new MA applications for products to be authorised via the centrally authorised route require submission of a Risk Management Plan (RMP) to EMA. The RMP should describe the risk management system and contain information regarding identified risks, potential risks and missing information (for example drug exposure during pregnancy or use of the medicinal product in specific patient populations that have not been exposed to the product before). It should outline any risk minimisation measures adopted and include information about the effectiveness of these measures. The RMP must be updated as new significant information affecting the benefit-risk of the product(s) emerges. The MAH may be required to conduct post-marketing authorisation studies to identify or evaluate additional safety and/or efficacy information or maintain a registry to collect safety information on known or potential risk factors for the product(s). Major identified risks, where they impact on the risk/benefit ratio of the product, may result in a change to the existing marketing authorisation. Within the EU, products constituted or derived from stem cells, tissue engineering or gene therapy technologies are classified as Advanced Therapy Medicinal Products (ATMPs). These require additional risk management considerations for detection and monitoring of safety and efficacy which must be described within the RMP.
The MAH should have robust signal management processes in place to detect and evaluate new safety signals that could have an impact on patient safety. It is expected that the MAH will work in accordance and in collaboration with the EU signal management process, for which the Pharmacovigilance Risk Assessment Committee (PRAC) has oversight. Signal management applies to all authorised products within the EU including nationally approved products. A signal is defined as a new potentially causal association or new aspect of a known causal association with a medicinal product. The information can come from any source and the MAH must follow the processes involved. This entails detection, prioritisation, validation and assessment of the signal to determine the impact on the existing risk-benefit profile of the product. A validated signal must undergo further assessment to review the impact on the risk-benefit profile of the product. Confirmed signals are signals that, after analysis of all the available evidence, establish a new causal association or new aspect of a known association. If it is identified as an emerging safety concern that could have an impact on the risk-benefit balance of the product or have implications for public health, this could lead to regulatory action and urgent communication of the new risk with prescribing HCPs and patients. Regulatory action could entail changes to the prescribing information, additional risk management obligations, restricted use of the product or withdrawal from the market.
Global Literature Search Strategy
It is required that upon submission of a MA application, the MAH will conduct regular (at least weekly) searches of the medical and scientific literature to identify any emerging safety information. Local (non-indexed) literature searches may also be required to review journals relevant to the therapeutic area or patient population. Literature searches should be constructed in such a way to identify both Individual Case Safety Reports (ICSRs) of ARs and relevant safety information (e.g. class effects) for consideration in periodic reports.
The EMA also screen global literature for ARs associated with certain EU authorised products via the Medical Literature Monitoring (MLM) service. The MAH should monitor and download ICSRs for their products where these are included in the MLM list of products.
The MAH must be registered within the EMA’s EudraVigilance (EV) database to send and receive ICSRs and maintain the eXtended EudraVigilance Medical Product Dictionary (XEVMPD) also referred to as the Article 57 database. The MAH must register in EV the details of the organisational headquarters, the QPPV contact details, the location of the PSMF, as well as information on EEA authorised products in XEVMPD. Where electronic submission of ICSRs to EV is to be conducted directly from the MAH’s database via a gateway, testing of the MAH’s database with EMA is required to verify accuracy and completeness of submissions made subsequently. The MAH must also be registered with the EudraVigilance Data Analysis System (EVDAS) to download outputs on all ARs within EudraVigilance for their product(s) for signal management purposes.
This article provides a brief overview of the key requirements for establishing a PV system in support of authorised products within the EU. The European framework for PV is comprehensive and does provide a good basis for meeting requirements outside the EU but there are specific requirements in other territories that are not covered by EU requirements. Furthermore, there are specific additional requirements within the EU at a national level that need to be met. The EMA provide guidance within the Good Pharmacovigilance Practice (GVP) modules which cover the PV requirements within the EU. Establishing a PV system can be a complex, resource and time intensive and costly endeavour. Increasingly, many companies choose to out-source part or all of the PV activities to third party PV providers. While this can enable faster set-up and reduced costs, the MAH retains ultimate responsibility for all the PV activities and the safety of their products. Therefore, when delegating any activities to a PV provider, whilst cost is always an important factor, it is vital to undertake continuous due diligence (e.g. via audits) of the provider to ensure their systems and processes are maintained, robust, compliant and validated (IT systems). Furthermore, the MAH must ensure that staff are appropriately qualified, experienced and trained to perform their roles.
QVigilance is committed to delivering quality-driven pharmacovigilance services and working flexibly and collaboratively with our customers. For further information on PV requirements for the EU or beyond, or to discuss outsourcing services, please contact the team at firstname.lastname@example.org or visit our website www.qvigilance.com