Safety updates

Updated 22 March 2021

What is a periodic safety update report (PSUR)?

A periodic safety update report (PSUR) is a report that provides an updated overview of the benefits and risks of a medicine.

The report, which marketing authorisation holders are required to submit to the EMA, must include:

a list of the adverse reactions known to the company,
an estimate of the number of humans exposed to the medicine,
an overall safety evaluation of the medicine,
proposals for new safety measures, if relevant.
an overall evaluation of the medicine’s benefits,
a scientific evaluation of the medicine’s benefit/risk ratio based on the total data from primarily clinical trials, the scientific literature and reports of side effects.

When must the PSUR be submitted?

The European Medicines Agency (EMA) has published a list of submission dates and frequencies for the submission of periodic safety update reports (PSURs). This list is known as the EURD list. The EURD list is a list of active substances and combinations of active substances contained in medicinal products authorised under different procedures (national procedure, mutual recognition procedure, decentralised procedure, centralised procedure) in the EU. The list provides the EU reference date, frequency for submission of PSURs and related data lock point (DLP) (defined as the cut-off date for data to be included in a PSUR), as well as the EU member state responsible for assessment of the submitted PSUR(s) for each active substance or combinations of active substances.

The information provided in the EURD list for a given active substance or combination of active substances takes effect six months after the publication date of the list.

Marketing authorisation holders are required to submit PSURs according to the dates published in the EURD list. The EURD list overrules the PSUR frequency and DLP described in Article 107c (2) of Directive 2010/84/EU, and any other conditions provided in the marketing authorisation.

If the active substance/combination of active substances is not on the EURD list, the PSUR frequency described in Article 107c (2) of Directive 2010/84/EU is followed:

every six months following authorisation in Denmark and until the placing on the market,
every six months during the first two years following the initial placing on the market,
once a year for the following two years,
at three-yearly intervals thereafter.

How is a PSUR submitted?

The marketing authorisation holder must use the PSUR repository as the only means of submission and must not send PSURs to the individual national competent authorities. It is mandatory to use the PSUR repository for products authorised under the central, national, mutual recognition and decentralised procedures regardless of whether the PSUR is part of an EU single assessment procedure or if the PSUR follows a national procedure. PSURs that have not been sent to the PSUR repository are considered as not submitted and will therefore not be assessed. PSURs not sent to the PSUR repository thus do not fulfil the marketing authorisation holder’s legal obligation to submit PSURs.

The PSUR repository is a common platform for storage and exchange of PSURs and related documents between the authorities and pharmaceutical companies in the EU. The platform was established based on the pharmacovigilance legislation as a means to promote the exchange of information between the authorities and pharmaceutical companies. The PSUR repository is intended for PSURs for human medicines only. You can read more about the PSUR repository here.

All PSURs are submitted to the PSUR repository via eSubmission Gateway/Web Client. To do so, marketing authorisation holders must register as a user via self-registration. PSURs must be submitted in eCTD format. Any other format will be rejected.

Prior to submission to the PSUR repository, marketing authorisation holders must ensure that the information on their authorised medicines is entered correctly in the Article 57 database. This is important because the information in the Article 57 database is connected to the PSUR repository. If the information about a product is not entered correctly in the Article 57 database, the PSUR cannot be uploaded. Correct updating of the Article 57 database is a legally binding requirement in the pharmaceutical legislation. You can find more information on the submission of medicines to the Article 57 database here.

Information on the PSUR repository together with guidelines and guidance videos on user registration, how to submit PSURs and required formats can be found here.

Questions concerning the PSUR repository and the eSubmission Gateway/Web Client should be directed to the EMA by contacting the EMA Service Desk portal.

Where are the results of PSUR assessments published?

Marketing authorisation holders are required to keep updated on their active substance(s) and to update their summary of product characteristics. This is also the case where routine PSURs are not required (for example in connection with generics (Article 10(1)) of Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use). This also includes updates following from the conclusions of PSUR assessments.

Single assessment procedures

The place of publication of the result of a single assessment procedure depends on the type of authorisation in the PSUSA procedure, see the table below.

Included in the PSUSA procedure	CAP products only	Both CAP and NAP products	NAP products only
PSUSA place of publication:	See the website of the EMA under the EPAR of the specific product	See the Community register	See the website of the EMA ‘Download medicine data’

Work sharing (WS) procedures

Single assessment has commenced for both CAP and NAP products, and therefore no new work sharing procedures are established.

The conclusions of PSUR assessments under work sharing are published at the website of the CMDh (Co-ordination Group for Mutual recognition and Decentralised Procedures – human).

Are routine submissions of PSURs required for products authorised pursuant to Articles 10(1), 10a, 14 and 16a?

No periodic safety update reports should be submitted routinely for the following medicinal products (see Article 107b (3) of Directive 2001/83/EC as amended):

generic medicines (Article 10(1) of Directive 2001/83/EC),
medicines containing an active substance for which well-established medicinal use has been demonstrated (Article 10a of Directive 2001/83/EC),
homeopathic medicines (Article 14 of Directive 2001/83/EC), or.
traditional herbal medicines (Article 16a of Directive 2001/83/EC).

PSURs are only to be submitted for the above medicines if it appears specifically from the EURD list. If the active substance of the generic medicine is not on the EURD list, the submission of a PSUR is only required if this was established in the marketing authorisation as part of the authorisation of the medicine, or if the Danish Medicines Agency has requested a PSUR.

Marketing authorisation holders of the above medicines are required to keep updated on the results of WS and PSUSA assessments. The marketing authorisation holders of generic medicines for which no routine PSURs are required must always notify the competent national authorities and the lead member state/PRAC rapporteur if they become aware of a new safety problem.

Is PSUR submission required for products that have been deregistered?

If the product has been deregistered after the submission date following from the EURD list, the submission of a PSUR is required irrespective of whether this is before or after the start date of the procedure.

If the product has been deregistered before the submission date specified in the EURD list, submission is not required unless this is specifically required by the national competent authorities.

How are the period safety updates assessed?

At the Danish Medicines Agency, we assess PSURs based on selected active substances with input from the other EU member states. In the assessment, we take into account:

has the PSUR been prepared as described in the GVP guideline module VII?
is the report of an acceptable professional quality and does the PSUR include a discussion of relevant results from clinical trials, scientific literature as well as reports of side effects?
do we agree with the scientific conclusions and any proposals for improving the safety of the product?
is the product’s safety profile reflected in the summary of product characteristics?
has the marketing authorisation holder provided us with sufficient information to assess the safety, or do we need additional material?

There are principally four outcomes of a PSUR assessment:

renewal of the marketing authorisation (not requiring any changes to the product information)
variation of the marketing authorisation (requiring changes to the product information)
suspension of the marketing authorisation
withdrawal of the product from the market

In the large majority of cases, the outcome is a renewal or a variation and only in very rare cases a suspension or product withdrawal.