Guideline on good pharmacovigilance practices (GVP) – Module VI – Collection, management and submission of reports of suspected adverse reactions to medicinal products (Rev. 2)

Overview of GVP Module VI (Rev 2)

This document, published by the European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA), provides detailed guidance on the collection, management, and submission of Individual Case Safety Reports (ICSRs) for medicinal products in the European Union (EU). It implements EU pharmacovigilance legislation and is based on international ICH guidelines (E2A, E2B, E2D).

Revision 2 (effective 22 November 2017) includes significant updates, particularly to align with the new EudraVigilance system and simplified reporting requirements.

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Key Sections of the Guideline

1. VI.A. Introduction & Terminology

• Purpose: Outlines the legal basis (EU Directives and Regulations) and the scope of the module.
• Key Definitions: Provides crucial definitions for consistent interpretation, including:
  • Adverse Reaction vs. Adverse Event: An adverse reaction is a suspected causal response to a medicine.
  • Seriousness: Criteria for classifying a reaction as serious (e.g., death, life-threatening, hospitalization).
  • ICSR (Individual Case Safety Report): The format for reporting a single case. A valid ICSR must contain at least:
    1. An identifiable reporter
    2. An identifiable patient
    3. A suspected medicinal product
    4. A suspected adverse reaction
  • Special Situations: Defines terms like overdose, off-label use, misuse, abuse, medication error, and occupational exposure.

2. VI.B. Structures and Processes (General Principles)

This section describes the core activities for handling safety reports.

• Collection: Distinguishes between:
  • Unsolicited Reports: Spontaneous reports from healthcare professionals/consumers, literature reports, and digital media reports.
  • Solicited Reports: Reports from organized systems like clinical trials, patient support programs, and post-authorization studies.
• Validation: Emphasizes that only reports meeting the four minimum criteria (listed above) are valid for submission.
• Follow-up: Stresses the need to seek additional information for incomplete reports, especially for serious cases, pregnancy reports, or cases of special interest.
• Data Management: Requires data to be handled confidentially, accurately, and with full audit trails.
• Quality Management: Mandates that Marketing Authorization Holders (MAHs) and Competent Authorities have a Quality System with Standard Operating Procedures (SOPs) and trained staff.
• Submission Timeframes:
  • Serious ICSRs: As soon as possible, but no later than 15 calendar days from receipt.
  • Non-Serious ICSRs (in the EU): 90 calendar days (see section VI.C.3).
• Electronic Submission (ICH-E2B): ICSRs must be submitted electronically using internationally agreed formats (ICH-E2B) and terminologies (MedDRA).

3. VI.C. Operation of the EU Network (EU-Specific Requirements)

This is a critical section detailing how the rules are applied within the EU regulatory framework.

• Responsibilities:
  • Marketing Authorization Holders (MAHs): Must collect and report all suspected adverse reactions from anywhere in the world related to their products authorized in the EU.
  • Competent Authorities (e.g., National Agencies): Must collect reports occurring in their territory and operate national reporting systems.
• EudraVigilance Database: The central EU database for managing ICSRs.
  • EVPM (Post-Authorisation Module): For ICSRs from the post-approval setting.
  • EVCTM (Clinical Trial Module): For SUSARs (Suspected Unexpected Serious Adverse Reactions) from clinical trials.
• Key EU Submission Rules:
  • MAHs submit all serious ICSRs (from within and outside the EU) and all non-serious ICSRs from the EU to EudraVigilance only.
  • Competent Authorities submit all ICSRs (serious and non-serious) reported directly to them in their territory to EudraVigilance.
• Special Topics: Provides specific guidance on handling reports from:
  • Literature (with exclusions for certain types of articles)
  • Medication errors
  • Lack of efficacy (for certain products like vaccines)
  • Pregnancy and breastfeeding
  • Off-label use
  • Falsified medicines and quality defects

4. Appendices (Practical Implementation)

The appendices offer detailed business process maps and descriptions for operational activities:

• Appendix 1: Process for the follow-up of ICSRs.
• Appendix 2: Detailed guidance on monitoring medical literature for case reports.
• Appendix 3: Modalities for the submission of ICSRs in the EU.
• Appendix 4: Submission of ICSRs to the World Health Organization (WHO).
• Appendix 5: Nullification of cases (declaring a report void).
• Appendix 6: Data quality monitoring.
• Appendix 7: Duplicate detection and management of ICSRs.

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Conclusion

GVP Module VI is the comprehensive rulebook for the handling and reporting of individual adverse reaction cases in the EU. It ensures that safety data is collected, validated, and submitted in a standardized, high-quality, and timely manner to EudraVigilance, enabling robust signal detection and continuous assessment of the benefit-risk balance of medicines across the European Union.