Pharmacovigilance

Pre-Authorisation

During the development of a new medicinal product, pharmaceutical companies must establish a PV system to collect and assess all adverse events (ADEs) associated with the product. Adverse events meeting the criteria for “serious” must be reported to Regulatory Agencies and other physicians (Investigators) who are conducting clinical trials with the same drug substance (see SUSAR submissions below).

How can we help?

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 provide flexible services that are fully adaptable to a client’s particular needs. 

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. 

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• Safety Management Plans (SMP)

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  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 define the responsible persons for all 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.

  How can we help?

  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.

• Serious Adverse Event (SAE) Processing

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  It is the legal responsibility of the clinical trial Investigator to send “serious” adverse events (SAEs) to the sponsor within 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. 

  How can we help?

  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.

• Suspected, Unexpected Serious Adverse Reaction (SUSAR) Submissions

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  “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, by which means 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 calendar days and all other SUSARs within fifteen days.

  How can we help?

  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. We also establish and implement compliant reporting systems to Ethics Committees and Investigators who do not have this electronic reporting functionality.

• Post-Authorisation Safety Study (PASS) & Drug Utilisation Study (DUS)

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  In recent years, the requirement for a PASS or DUS following an MA has become increasingly common. 

  • A PASS is carried out to obtain further information on a medicine's safety, or to measure the effectiveness of risk-management measures.
  • A DUS describes how a medicinal product is prescribed and used in real-life clinical practice and characterizes the population of patients who are prescribed the product.

  A synopsis of the required study must be submitted before the MA is granted and a full protocol must be submitted shortly afterwards.

  How can we help?

  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 Review Meetings

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  Sponsors of developmental and marketing authorisation holders of marketed medicinal products are required to continuously monitor the safety of their product 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.

  How can we help?

  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.

• Development Safety Update Reports (DSUR)

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  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.

  How can we help?

  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 uptodate safety status for a given drug in line with GVP guidelines. 

Post-Authorisation

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). 

How can we help?

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.

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• EEA Qualified Person for Pharmacovigilance (EEA QPPV)

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  It is a legal requirement within the European Union to have a Qualified Person for Pharmacovigilance (QPPV) who is responsible for the following PV activities for an authorised medicinal product:

  • establishing and maintaining the Marketing Authorisation Holder's PV system
  • promoting, maintaining and improving compliance with the legal requirements relating to PV
  • an overview of medicinal product safety profiles and any emerging safety concerns (including having an awareness of conditions or obligations as part of the MA) and of risk minimisation measures (including the content of the RMP)
  • acting as a single point of contact, on a 24-hour basis, for the EMA and regulatory authorities
  • ensuring the PSMF file is up-to-date and accurately reflects the PV system.

  How can we help?

  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.
   

• Pharmacovigilance System Master File (PSMF)

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  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. 

  How can we help?

  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.

   

• Safety Data Exchange Agreements (SDEA)

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  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.

  How can we help?

  EUDRAC produces suitably detailed and effective SDEAs for its clients, these have been received positively and with praise by regulatory inspectors and auditors.

• ADR Processing

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  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. 

  How can we help?

  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. 

• Literature Screening

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  Medical literature is a significant source of information to be reviewed when monitoring the 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.

  How can we help?

  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.

   

• Post-Authorisation Safety Study (PASS) & Drug Utilisation Study (DUS)

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  In recent years, the requirement for a PASS or DUS following an MA has become increasingly common. 

  • A PASS is carried out to obtain further information on a medicine's safety, or to measure the effectiveness of risk-management measures.
  • A DUS describes how a medicinal product is prescribed and used in real-life clinical practice and characterizes the population of patients who are prescribed the product.

  A synopsis of the required study must be submitted before the MA is granted and a full protocol must be submitted shortly afterwards.

  How can we help?

  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. 

• Signal Management

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  Safety signals are “new or updated information” on adverse effects 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 benefit: risk profiles can be generated or modified as necessary.

  The following principles should apply when performing signal detection and developing a benefit: risk profile:

  • An appropriate data set of adverse drug effects should be generated (using statistical tools on relevant safety data sets)
  • Data from all sources should be considered 
  • The quality and integrity of the data and signal detection activity must be high
  • Qualified and trained personnel should review cumulative data in a timely manner
  • The process should be adequately documented, with rationale for the method and periodicity of the activity

  How can we help?

  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.

• Safety Review Meetings

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  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.

  How can we help?

  EUDRAC organise, lead, and document safety review meetings for our clients. We provide both regulatory and PV advice on drug safety requirements.

• RMP Maintenance

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  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.

  How can we help?

  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 Safety Update Report (PSUR)

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  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.

  How can we help?

  EUDRAC is involved in full PSUR data collection, writing and reporting (to all required parties) as part of our pharmacovigilance service for our clients.

Database & Processing

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.

How can we help?

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.

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.

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• Pharmacovigilance Database

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  Pharmacovigilance (safety) databases must be fully validated to meet ICH E2B requirements in order to effectively process and submit ADR data.

  How can we help?

  EUDRAC uses the validated Pharmacovigilance Manager (PcV) system as the single safety database for the all PV information relating to:

  • Adverse reactions related to authorised medicinal products 
  • Serious adverse events arising from clinical trials

  The PcV Manager is developed by Extedo GmbH and consists of a Microsoft SQL Server which uses open reporting and querying technology for case safety reports including the following functionality:

  • Case processing(incl. coding [MedDRA], assessment, create CIOMS-Reports, Reconciliation), collection, storage, distribution and management of adverse events (AEs)
  • Full electronic submission of AE reports in E2B format

  The PcV Manager allows users to query, retrieve and data-mine information for a variety of purposes: 

  • Line listings
  • Signal detection and safety surveillance
  • Case analysis

   

• EudraVigilance Setup & Support

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  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:

  • Electronic exchange of individual case safety reports between EMA, NCAs, MAHs and clinical trial sponsors
  • Early detection and evaluation of possible safety signals
  • Better product information for authorised medicines

  Reporting information on ADRs and Serious AEs to the EudraVigilance system is mandatory.

  How can we help?

  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.

• Article 57(2) [XEVMPD] maintenance

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  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.

  How can we help?

  EUDRAC act as QPPV and holders of the PSMF for our clients, we also maintain the XEVMPD repository for their medicinal product portfolios.

Support

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 costs.

How can we help?

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 PV support.

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• Audits and Inspections

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  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. 

  How can we help?

  EUDRAC provides a full audit service also 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.

   

• Training

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  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.

  How can we help?

  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.

   

• QMS and SOP development

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  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.

  How can we help?

  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.