Though a lot of emphasis has been put on the vigilance activities for marketed pharmaceutical products, it is of utmost importance that the safety profile (as well as the efficacy parameters) for pharmaceutical products are establish as early as possible in the product’s life cycle. Promising drugs in a company’s pipeline must demonstrably show evidence of therapeutic benefit (i.e. the medicine is relatively safe to use and is effective for the targeted indication).
In recent years, pharmacovigilance has gradually moved from a reactive process to a more proactive outlook with an ultimate goal to protect, and safeguard public health. Pharmaceutical companies must, at a very early stage during the drug development process, establish a PV system to collect, evaluate, analyse and re-assess all adverse events (AEs) associated with the product. The pharmacovigilance pre-authorisation safety reporting requirements vary across individual Regulatory Agencies but generally, clinical trial sponsors must ensure that serious adverse events (SAEs) that are deemed to be related (with a list a reasonable possibility) to the study drug, and which are not listed when reviewed against the reference safety information must be reported to the Regulatory Agencies, Ethics Committees and other physicians (Investigators) who are conducting clinical trials under the same protocol, or with the same drug substance in a different study with the same trial sponsor(see SUSAR submissions below).
The changes in regulatory requirements particular in the pharmacovigilance sector present a challenge for trial sponsors. Small and Medium-sized Enterprises (SMEs) in particular struggle to keep up to date with changing regulations and requirements. Depending on the product and clinical phase of development, the resources for PV activities for clinical trials can vary quite significantly. Clients who outsource PV activities to EUDRAC reduce the associated workload and expense by utilising our specialist PV team and our established systems and procedures. EUDRAC provides flexible services that are fully adaptable to a client’s particular needs. Outsourcing to EUDRAC PV provides an attractive option for trial sponsors especially SMEs because administrative burdens associated with the set-up, maintenance and oversight of a functioning PV department are negated or are significantly reduced (dependent on the clients’ requirements).
Our team supply all pre-authorisation and clinical PV services, we also conduct regular PV intelligence reviews and training for our clients; we provide specific support for audits and inspections.
Safety Management Plans (SMP) or Safety Data Exchange Agreements (SDEA) are the key to successful interactions between clinical trial sponsors and their PV Partners.
A good SDEA should clearly delineate the roles and responsibilities for all the PV activities between the parties concerned. It must ensure that there is effective communication between data management and clinical operations teams and provide complete clarity on the information flow for all safety information. There must be absolute assurance that all safety information will be captured and reported appropriately.
EUDRAC prides itself on producing suitably detailed and highly effective SMPs and SDEAs, which have been received positively and with praise by inspectors and auditors during regulatory inspections and both internal and external audits.
It is the legal responsibility of the clinical trial Investigator to send “serious” adverse events (SAEs) to the sponsor within one (1) calendar day. The sponsor must capture and process this SAE report and all relevant information relating to the SAE must then be sought until its resolution.
The processing of SAEs must be efficient, effective and allow for ease of assessment. The information about an SAE must be contained within a suitable safety database and documented in a regular and structured fashion.
EUDRAC operates a well-established and inspection-ready process for SAE data. Our safety database and set of Standard Operating Procedures are currently used to process SAEs from a wide range of developmental products and clinical phases.
“Serious adverse events” which are considered to be “at least possibly related” to a medicinal product are considered to be “serious adverse reactions”. If they are “unexpected, [meaning that they are not included in the Reference Safety Information (usually the Investigator Brochure in a clinical trial)], they are also classified as “unexpected”.
If an “adverse reaction” is both “serious” and “unexpected” it is known as a “Suspected, Unexpected, Serious Adverse Reaction” or SUSAR. All SUSARs must be reported to NCAs (and the EMA in Europe), Ethics Committees and Investigators. Fatal and life-threatening SUSARs must be reported by the Sponsor within seven (7) calendar days and all other SUSARs within fifteen (15) days.
EUDRAC’s PV team establish the electronic reporting environments for our clients i.e. EudraVigilance and the routes between the relevant safety database and the NCAs and EMA as well as via Ethics Committee portals. We also establish and implement compliant reporting systems to Ethics Committees and Investigators who do not have this electronic reporting functionality. We have set-up audit- and inspection-ready submission trackers to ensure oversight and monitoring of all safety reports for compliance with regulatory requirements and in line with our overarching quality management key performance indexes (KPIs).
In recent years, the requirement for a PASS or DUS following an MA has become increasingly common.
A synopsis of the required study must be submitted before the MA is granted and a full protocol must be submitted shortly afterwards.
EUDRAC has written both the synopses and protocols for these studies for our clients. We have experience of the expected criteria and we also work with third-party providers who conduct the studies.
Sponsors of developmental and marketing authorisation holders of marketed medicinal products are required to continuously monitor the safety of their product and the Regulatory Authorities of any new safety information which may affect their products.
It is a key requirement, therefore, to conduct regular reviews of safety information affecting drug products, including safety review meetings with all key stakeholders.
As part of EUDRAC’s pharmacovigilance offering, we organise, chair, participate in and document regular safety review meetings.
EUDRAC organise, lead, and document safety review meetings for our clients. We provide both regulatory and PV advice on drug safety requirements.
Periodic analysis of safety information is an important part of the clinical development of a medicinal product. The DSUR is an annual report which provides an assessment of the up‑to‑date safety status for a given investigational drug in line with ICH guidelines.
The DSUR examines whether the information obtained by the sponsor during the reporting period is in accord with previous knowledge of the investigational drug’s safety; it describes any new safety issues that could have an impact on the protection of clinical trial patients and summarises the current identified and potential risks; including how they are managed. It also povides an update on the status of the clinical development programme and study results.
EUDRAC is involved in full DSUR data collection, writing and reporting services (to all required parties) as part of our clinical development service for our clients.
Periodic analysis of safety information is an important part of the ongoing maintenance of Marketing Authorisations for all drugs. The PSUR is a periodic report which provides an assessment of the up‑to‑date safety status for a given drug in line with GVP guidelines.
Risk management is the ongoing process of ensuring that the optimum benefit: risk profile for a product is maintained. The Risk Management Plan (RMP) is a dynamic document which outlines the risks and safety concerns associated with a medicinal product and the strategy being implemented to address these safety concerns and to minimise the risks.
The RMP is a key part of the MAA and reflects the safety information available on the drug. Data generated during the drug development process will be included in the RMP as well as plans to obtain further safety data after the authorisation is completed.
The clinical development at EUDRAC work alongside our clients to write the RMP for the MAA. We also assist our clients to develop Educational Materials and the design of PASS and DUS design, which are increasingly required as additional PV activities in an RMP.
In order to maintain Marketing Authorisations (MAs), pharmaceutical companies must have an established PV system which can monitor the safety of its authorised medicinal products and detect any change in their benefit: risk profile. This is a legal requirement.
The PV system must include the collection and assessment of ADRs, and incorporate such documents as the PV System Master File (PSMF), Periodic Safety Update Reports (PSURs) and the Risk Management Plan (RMP).
The resources required for PV activities can fluctuate throughout an MA. Clients who outsource PV activities to EUDRAC reduce the associated workload and expense by utilising our specialist PV team and our established systems and procedures. EUDRAC provide flexible services that are fully adaptable to a client’s particular needs.
Our team supply all post-authorisation and post-marketing PV services, we also conduct regular PV intelligence reviews and training for our clients; we provide specific support for audits and inspections.
It is a legal requirement within the EU to have a Qualified Person for Pharmacovigilance (QPPV) who is responsible for the following PV activities for an authorised medicinal product:
The EUDRAC PV team is led by trained and experienced QPPVs who act as designated QPPVs for our clients and also work with clients to establish a suitable PV system. All EUDRAC QPPVs have worked extensively in PV within the European Pharmaceutical Industry.
EUDRAC QPPVs also act as National Persons Responsible for Pharmacovigilance (NPRP – also known as local QPPVs or Local Contact Persons) and are the Primary Contact Person for the NCAs.
EUDRAC conduct audits of existing PV systems to EU PV regulations and guidance. We provide recommendations on established best practices and prepare our clients for NCA inspections.
The Pharmacovigilance system master file (PSMF) is a detailed description of the PV system. It is a dynamic document requiring regular update, particularly to the PSMF Annexes and provides a holistic overview of the PV system.
Over the years that we have been writing and maintaining PV systems and PSMFs for our clients, EUDRAC has established a well-documented set of best practices and processes designed to ensure great efficiency and compliance with PV regulations. From these, we have designed a Master, which we adapt for our clients or incorporate into their current PV system.
A Safety Data Exchange Agreement (SDEA) is a legal contract to ensure all safety data for a medicinal product (clinical trial and post-authorisation) is transferred to the MAH or clinical trial sponsor; this is a legal PV requirement.
A good SDEA should clearly define the responsible persons for all PV activities between the parties concerned. It must ensure PV regulatory compliance and there must be no uncertainty as to who is responsible for any of the PV activities.
The SDEA can be a stand-alone document or can be incorporated as part of a Master Service Agreement (MSA). It may be referred to by different synonyms such as Safety Management Plan (SMP). SDEAs can be requested for inspection by regulatory authorities and agencies.
EUDRAC produces suitably detailed and effective SDEAs for its clients, these have been received positively and with praise by regulatory inspectors and auditors.
It is a legal requirement for an MAH to capture all information relating to ADRs occurring throughout the lifetime of a medicinal product.
The processing of ADRs must be efficient, effective and allow for ease of assessment, the information about an ADR must be contained within a suitable safety database and documented in a regular and structured fashion.
EUDRAC operates a well-established and inspection-ready process for ADR data. Our safety database and set of Standard Operating Procedures are currently used to process ADRs from a wide range of authorised and developmental products.
Medical literature is a significant source of information to be reviewed when monitoring the risk-benefit: risk profile of a medicinal product. Information sourced from literature can lead to awareness of a new safety signal or emergent safety issue. Marketing authorisation applicants and holders are expected to perform literature screening based on criteria relevant to the product on at least a weekly basis.
EUDRAC have conducted literature screening for clients for a number of years. We have developed a structured system that provides consistent results for a wide variety of searches. Qualitative review and documentation by the PV team ensures all the required information is collected, stored and processed correctly.
In recent years, the requirement for a PASS or DUS following an MA has become increasingly common.
A synopsis of the required study must be submitted before the MA is granted and a full protocol must be submitted shortly afterwards.
EUDRAC has written both the synopses and protocols for these studies for our clients. We have experience of the expected criteria and we also work with third-party providers who conduct the studies.
Safety signals are “new or updated information” on an adverse effect that may be caused by a medicinal product. It is the responsibility of the MAH to perform frequent reviews of the available safety information on its products in order that risk profiles can be generated or modified as necessary.
The following principles should apply when performing signal detection and developing a risk benefit profile:
EUDRAC implement both a quantitative and qualitative approach to assessing signals and generating a risk profile. We implement a structured and planned system of: data collection, analysis and evaluation. This ensures that we always have up-to-date and accurate information affecting the benefit: risk profile of a medicinal product.
Sponsors of developmental and marketing authorisation holders of authorised medicinal products are required to continuously monitor the safety of their products and inform the Regulatory Authorities of any new safety information which may affect their products.
It is a key requirement, therefore, to conduct regular reviews of safety information affecting drug products, including safety review meetings with all key stakeholders.
EUDRAC organise, lead, and document safety review meetings for our clients. We provide both regulatory and PV advice on drug safety requirements.
Risk management is the ongoing process of ensuring that the optimum benefit: risk profile for a product is maintained. The Risk Management Plan is a dynamic document which outlines the risks and safety concerns associated with a medicinal product and the strategy being implemented to address these safety concerns and to minimise the risks.
EUDRAC writes and maintains RMPs for our clients; currently we are undertaking the transition to the new RMP Revision 2 template for a number of different drugs.
Periodic analysis of safety information is an important part of the ongoing maintenance of Marketing Authorisations for all drugs. The PSUR is a periodic report which provides an assessment of the up‑to‑date safety status for a given drug in line with GVP guidelines.
The PSUR examines whether the safety information obtained by the MAH during the reporting period is in accord with previous knowledge of the medicinal product’s safety; it describes any new safety issues that could have an impact on the protection of patients and summarises the current identified and potential risks, including how they are managed. It concludes with an update on the benefit: risk profile of the product.
EUDRAC is involved in full PSUR data collection, writing and reporting (to all required parties) as part of our pharmacovigilance service for our clients.
Marketing authorisation holders (MAHs) must implement measures to collect and collate all reports of suspected adverse reactions (ADRs) associated with their medicinal products. In addition, there are requirements for MAHs to submit ADRs to the European Medicines Agency (EMA) and National Competent Authorities (NCAs).
Therefore, a PV system needs to be established to ensure that MAHs correctly process all ADRs according to the EU regulations and guidance.
In recent years, regulators have begun implementing adaptive systems to ensure the optimal running of regulatory and pharmacovigilance activities through the standardisation of certain data elements to aid in the easy identification, review, and analysis of product-related safety issues.
EUDRAC operate a robust PV system; we have established PV processes and an experienced PV team to manage our safety database, and the processing and reporting of all PV data. We independently review pertinent PV regulations to ensure that we not only maintain compliance with regulatory requirements, but also ensure that our overarching quality management system is tailored adapt to changes within the regulatory landscape that may affect current practices and conventions.
Following a recent inspection by a major NCA, our PV system received zero critical and zero major findings; for further details see our Case Study.
Pharmacovigilance (safety) databases must be fully validated to meet ICH E2B requirements in order to effectively process and submit ADR data.
EUDRAC uses a validated safety database for the all PV information relating to:
EUDRAC PV holds the global safety database for some MAHs and acts as a local affiliate for other MAHs.
The safety database utilised by EUDRAC PV consists of a Microsoft SQL Server which uses open reporting and querying technology for case safety reports. This safety database is also complies with both the EU GMP Annex 11 and the US FDA CFR 21 Part 11 regulations, and has been validated against GAMP® 5: A Risk-Based Approach to Compliant GxP Computerized Systems.
EUDRAC PV have a team full of experienced MedDRA coders who can cover the end-to-end tasks involved within case processing which includes:
Our safety database allows users to query, retrieve and data-mine information for a variety of purposes:
EudraVigilance is a system developed and operated by the EMA for managing and analysing information on suspected ADRs to authorised medicines and SAEs to clinical trial medicines. The EMA operates the system on behalf of the European Union (EU) medicines regulatory network.
EudraVigilance supports the safe and effective use of medicines in the EEA by facilitating:
Reporting information on ADRs and Serious AEs to the EudraVigilance system is mandatory.
EUDRAC has set up EudraVigilance environments and user access for a large number of clients. As this can be a rate-limiting step for the implementation of PV systems, EUDRAC always works to ensure that this important process is completed as a key developmental milestone.
MAHs are required to submit information to the EMA on all their authorised medicinal products in the European Economic Area. The required process to convey this information is to update the eXtended Medicinal Product Dictionary (XEVMPD). In addition, information on the Qualified Person for Pharmacovigilance (QPPV) and the Pharmacovigilance System Master File (PSMF) must be uploaded to EudraVigilance and the XEVMPD.
EUDRAC act as QPPV and holders of the PSMF for our clients, we also maintain the XEVMPD repository for their medicinal product portfolios.
Pharmacovigilance systems require robust and effective quality management systems (QMS), controlled documents (including Standard Operating Procedures (SOP), & Work Instructions (WI)), specific training, and audits and inspections.
These support systems not only help an organisation meet regulatory legislation and guidelines, but also increase the efficiency and effectiveness of the PV system, thereby reducing associated.
EUDRAC has invested significant time and resources into the development of its support services. Our clients who utilise our range of services can take advantage of the expertise of the EUDRAC PV team and be confident that we always maintain up-to-date and fully compliant Pharmacovigilance support.
Pharmacovigilance audits and inspections provide an objective evaluation of the operation of a PV system. Good audits will provide an accurate measurement of the implementation of an organisation’s system against its procedures and the applicable legal requirements. They are a vital part of the QMS of an organisation and must be performed by suitably trained and experienced personnel.
EUDRAC provides a full audit service and prepares its clients for inspections conducted by NCA. We recently worked with a client undergoing an inspection by a major NCA, and received a very positive report; for further details see our Case Study.
It is a legal requirement that PV professionals are trained in the regulations and best practices of PV; they should have suitable knowledge and experience to set up and maintain a compliant and efficient PV system.
The EUDRAC PV team is led by two QPPVs and comprises qualified personnel with many years of PV experience in the pharmaceutical and medical device industry; we conduct customised training for our clients and also conduct regular PV intelligence updates. We ensure that both our own company and our clients are constantly up-to-date with all changes in the PV requirements.
Quality Management Systems, Standard Operating Procedures and Work Instructions are all necessary to ensure that an organisation operates in compliance with PV requirements. Due to the strict regulatory nature of the industry, best practices need to be established, documented and implemented.
EUDRAC works with clients to provide a suitable QMS and controlled documents for their medicinal products; we also provide training to ensure that these are operated in compliance with PV requirements.