On 20 June 2014, the European Medicines Agency (hereafter “EMA”) published a new European Union procedure on the management of pharmacovigilance inspection findings which may impact the robustness of the benefit-risk profile of the concerned medicinal products (“new EU Procedure”). The new EU Procedure came into effect on 1 June 2014.
One of the aims of the new European Union (“EU”) pharmacovigilance legislation, which entered into force on 28 October 2013, is to reinforce the harmonization of pharmacovigilance inspections in the EU. Furthermore, the new legislation aims to enhance cooperation among the relevant individuals and entities involved in pharmacovigilance inspections. These include the inspectors, the pharmacovigilance assessors in the EU Member States, the Pharmacovigilance Inspectors Working Group and the Pharmacovigilance Risk Assessment Committee (“PRAC”).
The Pharmacovigilance Inspectors Working Group consists of inspectors who are involved in conducting pharmacovigilance inspections. The Group is responsible for the development of EU procedures and guidance for pharmacovigilance inspections of the Marketing Authorisation Holders of medicinal products authorised in the EU.
In accordance with Good Pharmacovigilance Practices, the competent authorities of the EU Member States are expected to apply relevant EU procedures and guidance developed by the Pharmacovigilance Inspectors Working Group. They should also consider such procedures as the standard operating procedure for the quality systems established within the pharmacovigilance inspectorates of the EU Member States.
New EU Procedure
The new EU Procedure was adopted by the Pharmacovigilance Inspectors Working Group on 21 March 2014 and outlines the steps to be taken by the relevant individuals and entities involved in pharmacovigilance inspections in the EU.
The new EU Procedure specifically concerns the steps to be taken following the identification of inspection findings which may impact the robustness of the benefit-risk profile of medicinal products. In practice, these steps will vary depending on the potential impact of the inspection findings.
Inspection findings which may impact the robustness of the benefit-risk profile of medicinal products include findings which reveal:
• situations where the benefit-risk profile may be altered; and
• deficiencies in the pharmacovigilance system which have the potential to impact the safety profile of the medicinal product. Such deficiencies may include the failure by the Marketing Authorisation Holder to update risk-minimisation measures and/or the failure to communicate safety information to healthcare professionals and patients.
The new EU Procedure does not, therefore, address routine follow-up steps such as corrective and preventive actions undertaken by the Marketing Authorisation Holders.
Steps to be taken
First, the implementation of corrective and preventive actions taken by the Marketing Authorisation Holder should be assessed by the relevant inspectors during their follow up inspections. Improvements in the inspection findings must be assessed during these follow up inspections.
Second, following these inspections, the corrective and preventive actions taken by the Marketing Authorisation Holder and any impact assessments produced by the Marketing Authorisation Holder should be reviewed by the inspectors.
Third, depending on the seriousness of the inspection findings, the PRAC representative (for centrally authorised medicinal products) or the pharmacovigilance assessors (for medicinal products subject to a national marketing authorisation) must be notified of the inspection findings. The PRAC representative or the pharmacovigilance assessor will be required to assess the proposed corrective and preventive actions to be taken by the Marketing Authorisation Holder.
Review by PRAC
In certain situations, the PRAC representative or the pharmacovigilance assessor may decide to escalate the inspection findings to PRAC to assess the safety profile of the medicinal product. If the PRAC representative or the pharmacovigilance assessor consider that routine follow-up measures, such as Periodic Safety Update Report submission and signal detection activities, are not sufficient, the inspection findings must be escalated to PRAC. This will be the case if the inspection findings reveal that the safety and welfare of patients is, or has the potential to be, put at risk.
The lead inspector, in collaboration with the PRAC representative or the pharmacovigilance assessor, is responsible for providing the inspection findings to PRAC. To determine whether an assessment of the safety profile of the medicinal product by the PRAC is appropriate, the PRAC representative or the pharmacovigilance assessor may request additional information from the Manufacturing Authorisation Holder.
According to the new EU Procedure, the following inspection findings must be escalated to PRAC for assessment:
• findings which may challenge the established benefit-risk profile of the medicinal product or may have resulted in significant delays in introduction of appropriate risk-minimisation measures;
• findings related to the non-reporting of Individual Case Safety Reports data in significant volumes which may affect one or more medicinal products; and
• findings which may result in enforcement actions against the Manufacturing Authorisation Holder.
Following PRAC’s assessment of the inspection findings, the Manufacturing Authorisation Holder will be provided with the final PRAC advice which summarises the inspection findings and provides its recommendations concerning the follow-up measures to be taken by the Manufacturing Authorisation Holder.
These follow-up measures will be determined on a case by case basis by PRAC. However, they may include an assessment of the benefit-risk profile of the concerned medicinal products by PRAC.
Furthermore, if the Manufacturing Authorisation Holder fails to comply with inspection findings, and such failure results in harm to patients, enforcement action may be taken by the European Commission against the Manufacturing Authorisation Holder. Such enforcement action includes the imposition of financial penalties.
Inspection findings in relation to product labelling
According to the new EU Procedure, if the pharmacovigilance inspections reveal any failures in the maintenance of the Summary of Product Characteristics (SmPC) and the Patient Information Leaflet across multiple EU Member States, coordinated EU action may be required.
In these circumstances, the inspection findings should be provided to the relevant inspectors in the concerned EU Member States.
Depending on the seriousness of the failures, the Pharmacovigilance Inspectors Working Group may recommend the assessment of the inspection findings by the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) or PRAC.