Acronyms

  • ADR = Adverse Drug Reaction
  • CHMP = Committee for Medicinal Products for Human Use
  • CTD = Common Technical Document
  • EU = European Union
  • EEA = European Economic Area
  • EMEA = European Medicines Agency
  • EVMPD = Eudravigilance Medicinal Product Dictionary
  • GVP = Good Pharmacovigilance Practice
  • HCP = Healthcare Professional
  • ICSR = Individual Case Safety Report
  • MA = Marketing Authorisation
  • MAH = Marketing Authorisation Holders
  • MS = Member State
  • NCE = New Chemical Entity
  • PBRER = Periodic Benefit Risk Evaluation Report
  • PIL = Patient information leaflet
  • PRAC = Pharmacovigilance Risk Assessment Committee
  • PSMF = Pharmacovigilance System Master File
  • PSUR = Periodic Safety Update Report
  • PV = Pharmacovigilance
  • SmPC = Summary of Product Characteristics

Useful references

1. For more information on the GVP Guidelines, use this link: GVP Guidelines

2. Regulation (EU) No 1235/2010 – Of the European Parliament and of the Council of 15Dec2010

3. Directive 2010/84/EU – Of the European Parliament and of the Council of 15Dec2010

4. Commission Implementing Regulation (EU) No 520/2012 – on the Performance of Pharmacovigilance activities provided for in Regulation (EC) No 726/2004 and Directive 2001/83/EC

Non Standard Events Impacting Risk-Benefit

Some events do not fall within the definition of a reportable valid ICSR. However, these events may lead to changes in known risk-benefit balance of a medicinal product and or impact public health:

  • Major Safety findings from a newly completed non-clinical study 
  • Major Safety concerns identified in the course of a non-interventional post authorisation study or clinical trial 
  • Signal of a possible teratogen effect or of significant hazard to public health
  • Safety issues published in scientific and medical literature 
  • Safety issues arising from signal detection activities or emerging from a new ICSR and which impact on the risk-benefit balance of the medicinal product and/or have implications for public health 
  • Safety issues related to the use outside the terms of the marketing authorisation
  • Safety issues due to misinformation in the product information 
  • Marketing authorisation withdrawal, non-renewal, revocation or suspension outside the EU for safety-related reasons
  • Urgent Safety Restrictions outside the EU 
  • Safety issues in relation to the supply of raw material 
  • Lack of supply or interuption in supply of medicines

These events/observations which may affect the risk-benefit balance of a medicinal product are not to be submitted as ICSRs. They need to be notified as Emerging Safety Issues in writing to the competent authorities in Member States where the medicinal product is authorised and to the Agency via email to: P-PV-emerging-safety-issue@ema.europa.eu Immediate notification is required, indicating points of concern and actions proposed.

These ‘Emerging Safety Issues’ should also be discussed and analysed in relevant sections of PSUR of authorised medicinal product.

Fundamental Responsibilities

The simplest way to summarise the obligations of the pharmaceutical company are:

  • A system for collection and recording of all suspected adverse reactions should be implemented.
  • Follow up investigations for case reports should comply with data protection legislation.
  • PV data and documents must be retained by the MAH for as long as the product is authorised and for at least 10 years after the licence has expired. Union or national laws may require an extension of this period.
  • Adverse reactions occuring in non-EU countries and related to at least one of active substances of any medicinal product for which the company holds an EU marketing authorisation, should be reported to the company in the EU, and if they belong to the same mother company (or group of companies) should be reported to the global PV headoffice.
  • When a commercial agreement or partnership is formed with a non-EU company for a medicinal product which also holds an EU marketing authorisation, the clock starts when a valid ICSR is received by the non-EU affiliate/partner.

Collection and Recording of Reports

Each EU Member State (i.e. regulatory authorities) are required to have procedures for collecting and recording all reports of suspected adverse reactions made to them within their territory (i.e. AE reports sent to then directly from HCPs, Consumers and MAHs).

Data Archiving

PV data and documents should be retained for as long as the product is authorised and for at least 10 years after MA has expired, longer if union or national law requires.

Promoting Responsible Reporting

Each Member State (MS) is required to encourage HCPs and Consumers to report suspected adverse reactions and to acknowledge and provide further information if requested and available.

EudraVigilance

Valid ICSRs should be made available on EudraVigilance database for other Member States.

Electronic Transmission of ICSRs

ICH M2 EWB

The ICH M2 EWB defines the specifications to enable the exchange of an electronic common technical document (e-CTD) the focus of which is to enable the exchange of regulatory applications for marketing authorisations to occur between the pharmaceutical industry and regulatory authorities.

ICH E2B (R2)

Due to the large number of participants involved in the world-wide exchange of information related to adverse event reports, the ICH identified the need to implement a database that enables the direct exchange from database to database of this information.

Thus, the Electronic Transmission of ICSRs Message Specification was developed, which provides a common set of data elements and submission procedures to ensure the transmission of information is consistent, reliable and its integrity is maintained.

Electronic reporting of adverse events to regulatory authorities is now a mandatory requirement.

ICH E2B (R2) – Maintenance of the ICH Guideline on Clinical Safety Data Management: Data Elements for Transmission of ICSRs.

Maintenance of the ICH Guideline on Clinical Safety Data Management: Data Elements for Transmission of ICSRs.

ICH E2B Questions and Answers

This Q&A document provides answers to specific case related questions and scenarios submitted by pharmaceutical companies, regulators and vendors to clarify aspects of electronic reporting and the interpretation of the E2B guidelines.

ICH E2B Implementation Working Group – Questions and Answers (R5)

ICH E2B Implementation Working Group – Questions and Answers (R5)

Standard Medical Terminology

ICH MI Terminology

The International Conference on Harmonisation (ICH) is a multi-disciplinary group bringing together the regulatory authorities and the pharmaceutical industry of Europe, Japan and the United States.

MedDRA Term Selection

Medical Dictionary for Regulatory Activities (MedDRA) was implemented in 1999 and is open to all users. Most users are based in Europe, Japan and the USA, but worldwide use by regulatory authorities is growing.

MedDRA is a highly specific standardised medical terminology used to harmonise regulatory information for medicinal products. MedDRA is continuously enhanced and updated to meet the changing needs of regulators and the pharmaceutical industry.

ICH M1 (MedDRA Term Selection: Points to Consider Document) provides the latest version of the ICH-endorsed Guide for MedDRA Users.

For more information on MedDRA follow this link: MedDRA Dictionary

 

PRAC

The Pharmacovigilance Risk Assessment Committee (PRAC) is responsible for monitoring safety issues for human medicines and provides recommendations to the Committee for Medicinal Products (CHMP) on pharmacovigilance activities of medicinal products and on risk management systems, including monitoring of effectiveness of the those systems.

The PRAC members are nominated by EU member states together with the EMA management board. Members serve for a period of 3 years and are industry experts who represent healthcare professionals and patient organisations, with six independent scientific experts.

PRAC

For more details about the Pharmacovigilance Risk Assessment Committee follow this link.

Eudravigilance Medicinal Product Dictionary (EVMPD)

The EVMPD has been developed by the EMA and runs off the Eudravigilance online platform. The objective of the EVMPD was to define a specific format for the electronic submission of product information and to compile a complete list of all medicines authorised and registered in the EU.

This legislation came into force in December 2010 and requires all MAHs to continuously update their product information listed on the EVMPD.

Acknowledgement: Image taken as screen shot of Eudravigilance website.

 

European Medicines Web Portal

For communication and transparency the European Medicines Agency (EMA), sometimes referred to as “the Agency”, began publishing the agendas and minutes of all Pharmacovigilance Risk Assessment Committee (PRAC), Head of Medicines Agency (CMDh) and Committee for Medicinal Products for Human Use (CHMP) assessments, approvals recommendations and opinions through its corporate website, www.ema.europa.eu.

Beyond, 2012 the EMA plans to complete the development of a web portal which will link to all national competent authority portals.

Further strategies, design, functional requirements, management and maintenance of this portal are still to be defined.

European Medicines Agency

For more information about the European Medicines Agency (EMA), follow this link.

Acknowledgement: Image taken as screen shot of EMA website.