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Pharmacovigilance - questions and answers

Updated 02 December 2013

Which executive orders form the basis for inspections?

The current and most important executive orders forming the basis for inspections are executive order no. 822 of 1 August 2012 on monitoring of adverse reactions from medicinal products issued by the Ministry of Health.

Ministry of Health: (Previously Danish Medicines Agency) Executive order no. 1214 of 7 December 2005 on requirements for the layout of adverse reaction reports and periodic safety update reports etc.

Ministry of Health: (The Danish Health and Medicines Authority) Executive order no. 826 of 1 August 2012 on the reporting of adverse drug reactions from medicinal products etc.

Ministry of Health: Executive order no. 825 of 1 August 2012 on non-interventional safety studies, EU Regulation no. 1235/2010 of 15 December 2010, including Commission Implementing Regulation (EU) No. 520/2012 of 19 June 2012.

The current version of the European Medicines Agency's Good Pharmacovigilance Practices

Eudralex and Guidelines for pharmacovigilance for medicinal products for human and veterinary use Eudralex, Volume 9


How are companies selected for inspection?

The Danish Health and Medicines Authority (DHMA) makes a risk-based selection of companies subject to routine inspection.

The risk assessment covers for example:

  • Information provided by the companies to the DHMA in a data form
  • Information about the quality and timeliness of submitted adverse reaction reports, periodic safety update reports from marketing authorisation holders, Risk Management Plans etc. to the DHMA
  • The risk profile of the marketed medicinal products and whether they are comprised by increased safety surveillance
  • Inspection status, including information about when the marketing authorisation holder (MAH) was most recently inspected and the result of the inspection


Are there any special focus areas in connection with an inspection?

In connection with the new pharmacovigilance legislation, the DHMA focuses on whether the MAH has implemented the new rules, and to the extent that it has not taken place – the MAH's plans for the implementation.


What is being inspected at an inspection?

  • The pharmacovigilance system and accompanying quality management systems
  • Handling of adverse reaction reports (ICSRs)
  • Preparation of periodic safety update reports (PSURs)
  • Handling of information on adverse reactions from intervention and non-interventional trials (if relevant)
  • Signal detection and risk management


How many inspections have been conducted?

So far, the DHMA has conducted around 60 pharmacovigilance inspections. Some MAHs have been inspected several times, others have not been inspected. In addition to pharmacovigilance inspections, the DHMA also inspects certain parts of the MAH's pharmacovigilance system in connection with other inspections, such as GMP, GDP and GCP inspections.


What are the conclusions of the inspections?

Almost all of the inspected companies have a pharmacovigilance system with an accompanying quality management system. The challenge is often to ensure ongoing development of the system and its users according to the current requirements. However, a number of deviations from legislation and guidelines were found, of which the most frequent and/or most important ones are mentioned below.


What frequent/important deviations were found on the inspection of quality management systems?

  • Lacking, incomplete, incorrect and outdated standard operation procedures (SOPs)
  • Lack of all types of documentation, including the documentation for important decisions
  • Deviations were not handled in accordance with the description in the deviation system
  • Inadequate follow-up on the causes for adverse reaction report submitted too late
  • Auditors do not have sufficient experience in pharmacovigilance and subsidiaries have not been audited


What frequent/important deviations were found on the inspection of facilities?

  • Inadequate access control to archives
  • The filing period is not described in procedures or is too short
  • The MAH cannot receive reporting of adverse reactions etc. 24/7
  • Cases that were not filed in the MAH's archives/database


What frequent/important deviations were found on the inspection of the MAH's description of the pharmacovigilance system, also known as Detailed Description of the Pharmacovigilance System/Pharmacovigilance System Master File (DDPS/PSMF)?

  • Documents are lacking or incomplete
  • The document does not reflect the actual pharmacovigilance system
  • Annexes to PSMF are incomplete, not updated or not delivered. This applies to e.g. annexes about distributors, partners, system performance etc.


What frequent/important deviations were found on the inspection of the issue "organisation and staff"?

  • The qualified person responsible for pharmacovigilance (QPPV) is not adequately qualified and/or has insufficient overview
  • The qualified person responsible for pharmacovigilance (QPPV) does not have access to consult medically trained staff
  • Inadequate resources to ensure compliance with current legislation
  • Not all employees have been trained in pharmacovigilance
  • Training not documented
  • Job descriptions and areas of responsibility were not clearly defined
  • No cover for critical functions in connection with holidays


What frequent/important deviations were found on the inspection of the issue "documentation for adverse reactions"?

  • Adverse reaction reports are not processed and submitted on time (all levels)
  • Under-reporting, excess reporting, erroneous reporting
  • No follow-up on adverse reaction reports or follow-up made at a very late stage
  • Insufficient checking for duplicates
  • Inadequate evaluation of adverse reaction reports
  • Adverse reaction reports were not submitted electronically
  • Adverse reaction reports were not submitted to all the relevant parties
  • Inexplicable reclassification of adverse reaction reports
  • Wrong day 0, wrong reporting type etc.
  • No screening of the company's websites
  • No quality control of various pharmacovigilance activities, including e.g. translations


What frequent/important deviations were found on the inspection of the issue "periodic safety update reports (PSURs)"?

  • PSURs were not submitted on time
  • The contents of PSURs were not in accordance with legislation, for example there was no conclusion that new adverse reactions require a change to the summary of product characteristics.


What frequent/important deviations were found on with the inspection of the issue "maintenance of reference documentation"?

  • No procedures and deadlines for submission of safety variations
  • Safety variations were not submitted within the acceptable deadlines


What frequent/important deviations were found on the inspection of the issue "literature searching"?

  • Literature searching was not made in accordance with legislative requirements
  • Applied search criteria were not validated


What frequent/important deviations were found on the inspection of the issue "cooperation agreements"?

  • Missing contracts/agreements
  • Contracts did not comprise exchange of information about adverse reactions and/or time frames for exchange of information
  • Unclear distribution of responsibilities
  • Exchange of information on adverse reactions does not ensure timely reporting
  • Reconciliation of information about adverse reactions had not been made
  • Contracts did not secure possibility of audits

What frequent/important deviations were found on the inspection of the issue "audits"?

  • Contract organisations/collaboration partners were not audited
  • Conducted audits did not focus on the monitoring of adverse reactions
  • Pharmacovigilance was not comprised by the procedure for audits

What frequent/important deviations were found on the inspection of the issue "electronic systems"?

  • Systems with no possibility of tracing changes (audit trail) are used for critical processes
  • Audit trail was not or only partly readable
  • Systems were not validated or documentation for validation was missing
  • Differences between source data and data entered in the database
  • Inadequate reconciliation of information about adverse reactions between the pharmacovigilance database and other databases (for example about complaints, medical information, clinical trials)
  • Insufficient quality control of data entered
  • Insufficient access control to the electronic systems


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