Pharmacovigilance and inspections - questions and answers

Selection of companies for inspection?

The Danish Medicines Agency selects companies for routine inspection according to a risk-based approach. This means we decide how frequently a company should be inspected based on our assessment of patient safety risk.

The risk assessment includes:

• Information about the size of the company, the number of medicinal products on the market, changes in the company’s pharmacovigilance processes – e.g. relocation or a new qualified person responsible for pharmacovigilance (QPPV).
• Information about the quality and timeliness of submitted adverse reaction reports, periodic safety update reports, Risk Management Plans etc., which the companies have submitted to the Danish Medicines Agency.
• The risk profile of the marketed medicinal products and whether they are comprised by increased safety surveillance.
• Inspection status, including when the company was most recently inspected and the result of the inspection.

Scope and areas covered at an inspection

We make an individual assessment of the scope of each inspection and what areas it should cover. The most common areas covered are:

• The pharmacovigilance system and related 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.

Examples of typical deviations

Quality management systems:

• Lacking, incomplete, incorrect and outdated standard operation procedures (SOPs).
• Lack of documentation, including the documentation for important decisions.
• Deviations 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.

Facilities:

• Inadequate access control to archives.
• The filing period is too short or not described in procedures.
• It is not ensured that MAH can receive adverse reaction reports etc. 24/7
• Cases that were not filed in the MAH's archives/database.

Description of the pharmacovigilance system, also known as Detailed Description of the Pharmacovigilance System/Pharmacovigilance System Master File (DDPS/PSMF)

• Documents are missing or incomplete.
• Documents do not reflect the actual pharmacovigilance system.
• Annexes to PSMF are incomplete, not updated or not delivered. This applies to e.g. annexes about global and local distributors, partners, system performance etc.

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.
• Employee training is not documented.
• Job descriptions and areas of responsibility are not clearly defined.
• No cover for critical functions when employees are on leave.

Adverse reactions:

• Adverse reaction reports are not processed and submitted on time.
• 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.
• No explanation given for the 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 has been made, including e.g. translations. 

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.

Maintenance of reference documentation:

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

Literature searching:

• Literature searching was not made in accordance with legislative requirements.
• Applied search criteria were not validated.
• National literature searching was inadequate.
  A journal is considered relevant if its audience includes persons who are authorised to prescribe medicines and its content is scientifically relevant. Journals included in university library collections would normally be considered as scientifically relevant.

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.

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.

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.
• There are 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.