Risk-assessment questionnaire pharmacovigilance
To effectively monitor the compliance of Dutch marketing authorization holders with the Dutch and EU legislation, the Inspectorate has developed a Risk-Assessment Questionnaire Pharmacovigilance. The questionnaire contains questions about the organization in general, but also specific questions about the pharmacovigilance system. It is mandatory for all ‘Dutch’ MAHs to complete the survey.
In 2023 this online questionnaire should be completed on My IGJ via the unique URL link sent to the MAHs by email or letter. A template of the questionnaire can be downloaded using the link below. The downloaded template is to help MAHs during the collection of information from different departments or contractors, if necessary. The final questionnaire should still be completed and submitted via My IGJ.
Risk score per ‘Dutch’ marketing authorization holder
The information provided to the Inspectorate will be used to calculate a risk score and to determine an organization’s risk in comparison to other MAHs that have completed the questionnaire. These scores will be ranked and inspections prioritised for the companies with the highest risk scores.
A Dutch marketing authorization holder is considered to be any organization that holds an authorization which enables it to place a medicinal product on the Dutch market. This includes national, mutual recognition, decentralised and centralised licenses. The country of the location of the organisation does not determine whether or not they are a Dutch MAH.
The results of the risk-based pharmacovigilance (PV) survey 2020
On 20 January 2020, the risk-based survey was sent to the European Qualified Person of Pharmacovigilance (EU-QPPV) of all marketing authorization holders (MAHs) with a marketing authorization (MA) of human medicinal products in the Netherlands. All MAHs were requested to complete the survey within 3 months (13 April 2020 at the latest). Reminders were sent by e-mail to the MAHs which did not complete the survey before the deadline.
This survey was updated based on the results from the 2017 survey and the feedback that was received from MAHs. The main differences between the 2017 and 2020 surveys were:
- The survey was completed per PV system which included MAH-specific questions (previously: one survey per MAH)
- A number of questions were removed such as questions related to studies, programs and the number of fulltime-equivalent (FTE) per activity.
- Information regarding the Pharmacovigilance System Master File (PSMF) and Individual Case Safety Report (ICSR) compliance were removed, because these were retrieved from the eXtended Eudravigilance Medicinal Product Dictionary (XEVMPD) and the Eudravigilance database.
The contact details of the EU-QPPV were retrieved from the XEVMPD database. MAHs who have not submitted information on their MA in the XEVMPD database received a letter by post with the request to complete the survey. In addition, they were requested to submit information on their authorized human medicinal products in the XEVMPD database and keep this up-to-date (article 57(2) of Regulation (EC) No 726/2004).
In total, 684 surveys were sent of which 623 by e-mail and 61 by post. Altogether, 552 MAHs (80.7%) responded to the request and completed the survey. In total, 132 MAHs did not complete the survey. The figure below shows the different reasons for not completing the survey. Some of the 132 MAHs who did not complete the survey had a valid reason to do so. However there were also a number of MAHs who did not complete the survey without a valid reason.
Reason or non-completion of the survey
|in % N=132|
|Survey completed, but not received due to error||3|
|Not required because of type MA||0,8|
|No MA in NL (withdrawn or transferred)||9,1|
|Completed in other PV system survey (XEVMPD updated or incorrect)||8,3|
|Unknown (no response)||71,2|
|Second deadline has passed (May 2020)||0,8|
|No EU-QPPV or other (onknown) EU-QPVV||5,3|
Approximately 5% of the non-responders did not complete the survey because there was no EU-QPPV, because the EU-QPPV was unknown or the EU-QPPV is another person than the one registered in the XEVMPD database. There was one MAH that did not complete the survey because the deadline had passed and for 72% of the non-responders it was unknown why they did not complete the survey. Finally, 9% of the non-responders did not complete the survey because the survey concerning their PV system was already completed. MAHs who were included in the first three categories were allocated a higher risk score.
Changes of the EU-QPPV
As part of the pharmacovigilance system, all MAHs are required to appoint an EU-QPPV. MAHs were asked to provide the number of different EU-QPPVs that they had between 1 January 2018 and 31 December 2019. The figure below shows any changes of the EU-QPPV in the 2-year period for the 552 PV systems for which a survey was completed.
The number of changes of the EU-QPPV
|in % N=552|
|We do not have a QPPV||0,4|
|More than two EU-QPPV's||5,3|
According to the answers provided in the survey, 0.4% did not have a QPPV and 5.3% had more than 2 QPPVs during that period. These two groups were allocated a higher risk score than the other two groups.
Changes to the PV system
Changes to the PV system are a category of interest in the survey because they can be a risk for PV compliance. Examples include MAHs acquiring other MAHs integrating other PV systems, or changes in the safety database.
Of the 552 PV system surveys that have been completed, 121 (21.9%) MAs indicated that they had acquired other MAs by change of ownership between 1 January 2018 and 31 December 2019.
Changes to the PV system as a result of the acquisition(s)
|in % N=121|
|No significant changes||71|
|Minor orginazational and structural changes||29|
|Their PV system is integrated in your PV system||20|
The results show that 20% (n=24) of those who have acquired MAs by change of ownership, have implemented significant changes to their PV system. This group was allocated a higher risk score.
Changes to the global safety database
|in % N=552|
|Database migration (from another safety database to your database)||9,6|
|Changed into a new safety database||7,8|
The results show that 9.6% of the 552 responders had a database migration and 7.8% of the 552 responders had changed into a complete new safety database. Both groups were allocated a high risk score.
Compliance of timely PSUR and safety variation submissions
|Submitted on time||Total submitted|
|Safety variations submitted||230||315|
These results show that 315 out of 552 PV systems have submitted safety variations in that same period, of which 230 (73%) have submitted one or more safety variations on time. Furthermore, 285 out of 552 PV systems have submitted PSURs between 1 January 2018 and 31 December 2019, of which 251 (88.0%) have submitted on or more PSURs on time.
Those who have late submissions of PSURs or safety variations were allocated a higher risk score.
Outsourcing PV activities
MAHs may outsource PV activities to vendors, distributors or partners. The results below show the different activities that may have been outsourced. The number of vendors to whom it has been outsourced is provided per PV system.
PV activities outsourced
|Outsourced to one||Outsourced to two or more||Not outsourced|
|Audits (internal, external)||38,2||18,8||42,9|
|Risk management system (incl. production)||41,7||6,9||51,4|
|Database maintenace and support||70,3||5,6||24,1|
|Local literature searchin in NL||57,6||2||40,4|
|Global literature searching||65,4||4||30,6|
|Quality complaints processing||18,8||3,8||77,4|
|Providing medical information||35,7||10,1||54,2|
|National contact person in NL||50,2||0,7||49,1|
|EU qualified person for pharmacovigilance||44,7||0,2||55,1|
The figure above shows that activities involving audits, case processing and medical information enquiries are relatively often outsourced to 2 or more vendors compared to other activities. The more parties involved in an activity, the higher the risk. Therefore PV systems with activities that are outsourced to 2 or more vendors were allocated a higher risk score.
Audits and inspections
The survey also contains questions regarding audits and inspections of the PV system. The figure below shows the results that were provided in the survey.
Audits and (regulatory) inspection of the PV system
|PV system audit in the past three years||87,3||12,7|
The results shows that 63.8% of the PV systems have been inspected by a competent authority in the past and 87.3% have conducted an internal audit of their PV system in the past 3 years. Of the 200 (36.2%) PV systems that have never been inspected before, 23.5% PV systems have also not conducted an audit of their internal PV system in the past 3 years. This group was allocated a higher risk score.
External audits (distributors, partners) that have been conducted in the past 5 years
|in % N=492|
In total, 492 (89.1%) PV systems have agreements in place with distributors or partners who are subject to audits. Figure 8 shows that 18% of the PV systems have not audited any of their partners of distributors with whom an agreement is in place and who may be subject to audits. This group was allocated a higher risk score.
Results on a MAH level instead of PV system level
Information regarding the marketing authorizations in the Netherlands
The survey was completed on a PV system level, but within the survey, information regarding the MAs within the PV system were asked for each MAH. The total number of MAs in the Netherlands was provided which included centrally authorized products (CAPs) and nationally authorized products (NAPs, including those authorized via the mutual recognition procedure and decentralized procedure). According to the results provided in the survey, 770 MAHs (of the 552 PV systems) have MAs in the Netherlands at the time of completing the survey.
Information about the marketing authorizations in the Netherlands
|Traditional herbal, homeopathic medicinal products||2,6||69,1|
|Biologicals, biosimilars or vaccins||18,8||52,9|
The results in the figure above show the number MAHs with different types of products. Of the 770 MAHs, 2.6% have MAs for traditional herbal medicinal products or homeopathic medicinal products. Furthermore, 18.8% have MAs for biologicals, biosimilars or vaccines and 21.9% have MAs that are subject to additional monitoring. The latter two groups will be allocated a higher risk score.
The survey also contains questions regarding the marketing status of the MAs of the medicinal products in the Netherlands. In total, 479 (62.2%) MAHs have marketed one or more medicinal products in the Netherlands. Priority of inspections will be given to those who have marketed their products compared to those who have not marketed any of their products in the Netherlands.
MAHs with MAs with aRMMs
Risk-based inspections in 2021
The information collected in the survey in combination with the information retrieved from Eudravigilance (such as ICSR compliance) and the XEVMPD database will be used to make a risk profile for each MAH, together with other information that will be retrieved from Eudravigilance (such as ICSR compliance) and the XEVMPD database. These risk profiles are used as a tool to set up a risk-based national inspection program. The supervisory authority inspections are not within the scope of the risk-based national inspection program and will therefore be conducted as planned according to the inspection program of the EMA.