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Summary/Description of PV Systems and Risk-Based Inspections

Companies doing business or clinical trials in the European Union must prepare and have on file a critical document known as the Detailed Description of Pharmacovigilance Systems. It is described in Volume 9A. The equivalent in the United Kingdom is the Summary of PV Systems.

• Summary of PV Systems (Web Resource 49-1)
  
• Volume 9A—Guidelines on Pharmacovigilance for Medicinal Products for Human Use. Part 2.4 PV Inspections (Web Resource 49-2)
  
  
  
  • Section 2.2 Detailed Description of the PV System, Compliance Monitoring by the Competent Authorities and Pharmacovigilance Inspections

These documents are usually required in Marketing Authorizations submitted to the European Medicines Agency (EMA) or member states for approval of a drug and must be on file. They will be required for pharmacovigilance (PV) inspections by European Union-competent authorities. Companies not doing business or trials in the European Union do not need this document, as it is not required (yet) by other agencies. Nonetheless, it is a wise idea to prepare this document and update it periodically. By preparing it, the company will have a good idea of the status and quality of its PV systems. Some companies require this as part of their quality management systems.

The key parts of the DDPVS are noted here:

• 2.2.1 A detailed description of the pharmacovigilance system, including the proof of the availability of the services of the QPPV and the proof that the Marketing Authorization Holder has the necessary means for the collection and notification of any adverse reaction. It should contain an overview of the PV system with information on the key elements.
  
• 2.2.2 A signed statement from the MAH and the QP that the qualified person is available and responsible for pharmacovigilance and has the necessary means for the collection and notification of any adverse reaction occurring everywhere in the world.
  
• 2.2.3a) The name and contact information of the QPPV (24/7), with a CV, job description, and backup information.
  
• 2.2.3b) Location and identification of where the main EEA and global PV are done—particularly ICSRs and PSURs. Where PV data are accessible in the European Union. Organization charts and descriptions of the global and European PV units and their relationships. Licensing partnerships should be noted in an addendum. Flow diagrams showing how safety reports are processed.
  
• 2.2.3c) SOPs should be in place to cover the following processes and quality control to ensure their correct functioning:
  
  
  
  • QPPV and backup activities
    
  • The collection, processing, data entry, quality control, coding, classification, medical review, and reporting of ICSRs from solicited and unsolicited mechanisms, clinical trials, literature, healthcare professionals, sales and marketing, and other MAH, compassionate use, consumer reports, health agencies, and so forth, worldwide
    
  • Follow-up, detection of duplicates, electronic reporting, expedited reporting, PSURs
    
  • Global pharmacovigilance activities. Continuous monitoring of the safety of authorized products, signal detection, risk benefit assessment, reporting and communication to authorities, and medical professionals
    
  • Interaction between safety issues and product defects
    
  • Responses to requests for information from regulatory authorities
    
  • Handling of urgent safety restrictions and safety variations
    
  • Meeting commitments to agencies
    
  • Database handling and management
    
  • Internal auditing of the PV system
    
  • Archiving
    
  • Training
  
  
• 2.2.3d) Databases: A listing and description of the main PV databases used (compilation of safety reports, expedited and electronic reporting, signaling, sharing and accessing global data), a statement on their validation status, status of compliance with requirements for electronic reporting, a copy of the registration of the QPPV with EudraVigilance and identification of the process used for electronic reporting to competent authorities, who is responsible for operation of the databases and their location.
  
• 2.2.3e) Contractual agreements with outside organizations or persons, Including comarketing agreements and contracting out of PV activities, with a description of the nature of the agreements. Product-specific agreements may be listed in an appendix.
  
• 2.2.3f) Training: A description of the training systems and where the training records, CVs, and job descriptions are filed.
  
• 2.2.3g) Documentation: A description of the locations of PV source documents, including archiving arrangements.
  
• 2.2.3h) Quality Management System: A description of the system cross-referencing the functions noted in the other sections of the Description of PV Systems. Roles and responsibilities for the activities and documentation, quality control and review, and CAPAs should be noted.
  
• 2.2.3i) Supporting Documentation: Documentation on the PV system should be available during the pre- and postauthorization period.

This document is required by the United Kingdom’s MHRA. It is very similar to the European Union Description document described above. Key points and differences include:

• Companies should view the SPS as a living document and it should be kept up to date.
  
• Companies will have 6 weeks or so to prepare/update it when an inspection is due to occur.
  
• It should be no more than 25 pages (excluding appendices).
  
• Large companies with several divisions that are very different and have very different PV systems may need to prepare more than one SPS.
  
• The main focus is on the United Kingdom functioning.

The various sections of the document include:

• Section 1: Contacts and Licenses
  
  
  
  • Main United Kingdom contacts, where PV is done, QP contact information, company names and addresses if more than one product licenses are held in the United Kingdom under different company names.
    
  • Number of National and Centralized licenses held.
  
  
• Section 2: Company Structure
  
  
  
  • Company structure: holding/parent company, global subsidiaries, therapeutic areas and product portfolio, recent mergers or acquisitions
    
  • An overview of how PV is done.
  
  
• Section 3: PV Activities
  
  
  
  • A summary of the PV activities by the main PV site(s) in the United Kingdom and globally: “who, what, when, where, how, and why.” It should include but is not limited to: a summary of the PV activities performed by other departments (e.g., Medical Information, Regulatory Affairs, and Product Quality), the process for spontaneous and clinical trial ADR management—from receipt to data entry, review, and expedited reporting with flow diagrams(s), compliance monitoring activities, management and monitoring of clinical trial drug safety (including data reconciliation), PSUR preparation and submission, QP activities, processes for signal generation, trend evaluation and labeling changes, Risk Management Plans produced.
  
  
• Section 4: IT
  
  
  
  • The currently used local and global systems. Details of the databases/computerized systems used to collect, collate, and evaluate information about suspected ADRS (spontaneous, solicited, and trials), to include: whether the system was developed in-house or commercially and whether the system has been configured or customized following purchase; and validation status, location of the validation documentation, version details; who is responsible for system maintenance and support.
    
  • Historic situation: A summary of the legacy database used to collect, collate, and evaluate information over the last 5 years.
  
  
• Section 5: Quality Management System
  
  
  
  • If the Company intends to change the system within the next 6 months, provide a summary of the planned changes.
    
  • Indicate who is responsible for auditing the PV system and provide a description. How long audit reports are kept and where they are stored.
  
  
• Section 6: Training Records
  
  
  
  • Description of the United Kingdom training record system and the location of the records, CVs, and job descriptions.
  
  
• Section 7: Archiving
  
  
  
  • A description of the archiving activities for PV documents and if outsourced details of the company(ies) doing so.
  
  
• Section 8: Comments and Questions
  
  
  
  • Any additional assumptions, issues, etc., that are applicable.
  
  
• Appendices
  
  
  
  • Key personnel: organization charts for the United Kingdom and global PV and Medical Information (and contractors) departments, with names and job titles. CV and job description for QP and deputy.
    
  • Portfolio: All licensed products in the United Kingdom
    
    
    
    • Active ingredient(s), United Kingdom trade name; State if the product is not marketed in the United Kingdom; Method of approval (national, mutual recognition, centralized); Reference Member State (for mutually recognized products); Black triangle products; the five products that generated the greatest number of ADR reports in the last year.
    
    
  • Studies: A list of all ongoing phases I–III company-sponsored clinical trials that have at least one site in the European Union/EEA. A global list of all ongoing postauthorization clinical studies, including interventional clinical studies and noninterventional studies of United Kingdom-licensed products.
    
  • Quality Management System: Details of the global SOPs describing the content, format, approval, and review procedures for all levels of procedural documentation (i.e., SOP on SOPs), list of titles of all global, regional, and local PV procedural documents (e.g., policies, SOPs, and working instructions). A list of all other local documents that relate to PV (e.g., from Medical Information, Product Quality, Regulatory Affairs).
    
  • Regulatory Reporting—Compliance Statistics
    
    
    
    • For spontaneous expedited reports to the MHRA for the last 2 years, a monthly breakdown of: total ADR reports (nonserious and serious) received globally, total expedited ADR reports submitted to MHRA, total late reports submitted to MHRA, late reports as a percentage of the total number of expedited submissions to MHRA.
      
    • For clinical trial expedited reports to the MHRA for the last 2 years, expedited SUSARs submitted to MHRA, late SUSAR reports, number of late reports as a percentage of the total number of expedited submissions to MHRA.
      
    • PSUR reporting for last 2 years of PSURs to be submitted within 60 days of data lock-point: product, data lock-point, date submitted.
    
    
  • Third-Party Agreements (e.g., licensing, marketing, distribution, and CROs and other service providers of PV): A list of all United Kingdom and global agreements with third parties concerning marketed products and products not yet marketed/under development. Details of any activities/functions related to PV that are outsourced by the global PV group or in the United Kingdom (e.g., medical information, regulatory affairs, sales force, PSUR preparation, expedited reporting).
    
  • Product-Related Safety Issues: Details of any EEA products withdrawn from any global market in the last 5 years due to safety issues. Details of all Urgent Safety Restrictions in the last 2 years.
    
  • Document Requests to be Submitted with the SPS: Include a copy of the SOPs for:
    
    
    
    • Case processing of spontaneous adverse drug reaction reports
      
    • Case processing of clinical trial SAE reports
      
    • Follow-up of individual cases
      
    • Regulatory reporting of expedited reports to MHRA and EMEA
      
    • Monitoring of regulatory compliance with 7- and 15-day requirements
      
    • PSUR preparation and submission
      
    • Signal detection/trend analysis
      
    • Enquiry-handling by medical information function in the United Kingdom

Comments: Clearly, this is a major document with multiple appendices and data that must be obtained from many sources within the company that might not be handy or readily available to the PV department (e.g., holding company, global trials). This document should be prepared as a matter of routine, updated periodically, and kept on file. To prepare this in 6 weeks upon notification of an MHRA inspection can be a prodigious 24/7 effort.

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