Periodic safety update reports (PSURs)
The use of the PSUR Repository has become mandatory in the European Union on 13 June 2016.
The PSUR Repository is a common storage place for the PSURs, the regulators’ PSUR Assessment Reports, comments and final outcomes. Article 25a of Reg. (EC) 726/2004 required the Agency (in collaboration with the European Commission and Member States) to set up and maintain a repository for PSURs and corresponding assessment reports.
1. Where should MAHs submit PSURs?
All PSURs (with the exception of Art. 58 [WHO]) should be submitted directly to the PSUR Repository. This means that companies do not have to submit PSURs to multiple NCAs but should use the eSubmission Gateway / Web Client as a single point for all PSUR submission.
Please note that OGYÉI will reject all PSUR submissions, as there is no means to forward these documents to EMA. This applies to all PSUR submissions including PSURs prepared for products authorised exclusively in Hungary.
2. When must a PSUR be submitted?
PSURs have to be submitted for all medicines which are included in the EURD (European Union reference dates) list according to the conditions defined in the list (data lock points, submission deadlines and PSUR frequencies).
For medicines not included in the EURD list, PSURs should be submitted as specified in the marketing authorisation or otherwise according to the standard submission schedule of PSURs (i.e. six-month intervals, yearly and thereafter 3 yearly).
PSURs must be submitted according to the following schedule:
· within 70 calendar days of the data lock point for PSURs covering intervals up to 12 months;
· within 90 calendar days of the data lock point for PSURs covering intervals in excess of 12 months;
· the timeline for the submission of ad hoc PSURs requested by the national authority will be normally specified in the request, otherwise the ad hoc PSURs should be submitted within 90 days of the data lock point.
3. For which medicines do MAHs NOT need to submit a PSUR?
The requirement to submit PSURs is waived for
· generic medicinal products (authorized under the legal basis of Article 10(1) of Directive 2001/83/EC),
· WEU products (Article 10a),
· traditional herbal medicinal products (Article 16a) and
· homeopathic medicinal products (Article 14).
However, if considered necessary by the authority, PSURs for certain active substances will continue to be required, e.g. because the original drug was withdrawn from the market or safety issues emerged with the active substance. The EURD list indicates the active substances for which PSURs shall continue to be submitted on the above mentioned grounds.
The obligation to submit to the PSUR Repository does not apply to products that have been granted a scientific opinion under Article 58 of Regulation (EC) No 726/2004. For further information on how to submit PSURs for Article 58 products please refer to the guidance on Dossier requirements for Centrally Authorised Products (CAPs).
4. How should PSURs be submitted to EMA’s PSUR Repository?
The required submission format iseCTD(mandatory for all centrally authorised products) or NeeS. No other formats will be accepted for PSUR submissions.
In order to submit a PSUR to the PSUR Repository via the eSubmission Gateway / Web Client all users must register using the self-registration functionality. Further information how to register can be found here.
Guidance and training on how to submit PSURs can be found on the PSUR Repository webpage which contains detailed information on the steps required for the submission of PSURs. Further information is available on the eSubmission Gateway page.
All PSURs should be submitted with a delivery file which will provide metadata for the submission. The delivery file can be created on the PSUR repository MAH user interface. Detailed guidance on how to create and include the delivery file in your submission can be found from the MAH user guide and from the PSUR Repository website.
Information on the schedule and details of the EU PSUR Single Assessment Procedure (PSUSA) are published on the EURD list. The EURD list is linked to the PSUR Repository and only procedures for which the Data Lock Point has passed are available in the PSUR Repository. The EURD list also provides details on the procedure Lead Member State/Rapporteur and on the required legal basis for each procedure.
All marketing authorisation holders must submit information on the authorised medicines to the Art.57 database. PSUR repository product selection is connected to the Art. 57 database and if you are experiencing any issues with the product selection in the PSUR repository while creating the delivery file, please ensure that the product has been included in the Art. 57 database (XEVDMP). It is also important to ensure that all Art. 57 entries are correct with the products containing the correct legal basis as a built in business rule within the PSUR Repository will prevent products with incorrect legal basis being displayed.
Any PSUR in the EU Single Assessment Procedure needs to be submitted accompanied by the EMA template table cover letter as detailed in the Periodic safety update reports: questions and answers. MAHs may also use this cover letter to accompany submission of purely national PSURs to the PSUR Repository. Please note that only products selected via the user interface will be considered as part of the procedure.
Please note that PSURs submitted to NCAs will not be processed either as part of an EU Single Assessment Procedure, or as part of a purely National Procedure and will be automatically excluded from the procedure.
5. How should PSURs be submitted if there is a planned or unplanned downtime of the PSUR Repository?
If you encounter an issue with the PSUR Repository you should immediately report the incident through the EMA Service Desk Portal.
As soon as the EMA is aware of a system failure a communication to the Network will be launched and information published on the eSubmissions website and on the EMA Service Desk Portal. Status updates will be provided at regular time points, and the EMA will issue recommendations regarding the upload of procedural documentation and submission of PSURs. The system has built-in functionality to allow for the late submissions.
6. Where should queries or system failure be addressed concerning the PSUR Repository?
Users should contact EMA to report any incidents or defects they have with the PSUR repository through the EMA Service Desk Portal.
When proposing changes to system functionality, users should send their proposal to the PSUR Repository mailbox: PSURRepository@ema.europa.eu
Please note that procedural questions on non-EU single assessment procedures conducted only in one Member State1must be addressed to the relevant NCA.
For technical support with the EMA gateway/Web client, MAHs should contact the EMA Service Desk.
Frequently encountered issues:
A. The product cannot be found in the PSUR Repository user interface.
If you cannot find your product in the PSUR Repository this will most likely be due to the fact that the product has not been correctly included in the Art. 57 database. Please review the Art. 57 entry for your product to ensure it has been correctly included.
B. The procedure number for the EU single assessment cannot be found in the listing provided in the PSUR Repository user interface.
The PSUR Repository has been designed in such a way that MAHs can submit their PSURs only in the time window between the data lock point (DLP) and the EURD submission deadline. Any attempt to submit outside of this window will lead to the MAH not been able to find the procedure number. These business rules only apply however to the single assessment (PSUSA) procedure. For the non-EU Single Assessment there is no PSUSA Procedure number, and as such no requirement to include it when creating the XML delivery file.
7. How will MAHs be informed on the outcome of PSUR assessments?
MAHs do not have access to the PSUR Repository to perform search and retrieve activities; the preliminary assessment reports therefore need to be sent to them by the EMA via Eudralink. MAHs can request a Eudralink account through the EMA Service Desk Portal.
For publication of final conclusions, please refer to Question 9.
8. What are PSUFU procedures and how do they differ from PSUSA procedures in terms of submission requirements?
Occasionally, it may not be possible to finalise an issue (e.g. signal or new risk, where additional data is needed before the next PSUR) within a PSUSA procedure, but further scientific assessment of data is warranted. There are, several existing regulatory tools to handle follow-up requests: worksharing (WS) variation; signal procedure at PRAC level; bringing the next PSUR submission forward; initiating an appropriate referral procedure. However, all these options have their limitations.
Contrary to centrally authorised products (CAPs), no so-called LEG procedure exists for nationally authorised products (NAPs). This called for a new procedure to optimally handle such requests and to come to a consistent assessment of follow up requests. This procedure has been named PSUFU (PSUSA Follow-Up).
There is no legal basis for the PSUFU procedure; however, based on previous experience with the PSUR WS and synchronisation project MAHs and NCAs have agreed to cooperate in the PSUFU procedure and implement the outcomes. Therefore, based on the positive experience gained in the PSUR WS project the same principles for a WS procedure for PSUSA follow-up for NAPs has been applied.
A recommendation to initiate a PSUFU is made by PRAC and agreed by CMDh. The decision to initiate a PSUFU procedure is reflected in the final PSUR AR and will be published in the CMDh press release. The procedure number will be made available to the MAHs also via the CMDh Press Release, which is published on the CMDh website, together with the List of Questions (LoQ).
Submission route and requirements for MAHs
The MAH’s responses to a follow-up request should preferably be submitted via CESP (and in the future via CESSP). As CESP is not mandatory or accepted by all MSs, the documentation can alternatively be submitted to the individual MSs in accordance with their national submission requirements.
As PSUSA documents (both PSURs and ARs) are available to all MSs and the follow-up issue originated from the PSUSA, the submissions should be made to all MSs, regardless whether the MAHs hold a MA in the respective MSs. It is noted that the submission of follow-up information after a PSUSA through the PSUR repository is currently not possible.
Finally, the data submitted in relation to the PSUFU should be included in module 5.3.6. of the eCTD.
The initial request for follow-up data as made in the PSUSA AR (section 6. Other considerations) should describe to which MAH(s) the request is addressed (i.e. all MAHs that fall under the scope of the PSUSA, certain MAHs - for example due to product specific aspects or specific data available to them, or the brand leader MAH only).
For any further guidance, please refer to the CMDh website.
9. Where are PSUR assessment outcomes published?
Outcomes of PSUR single assessment (PSUSA) procedures concerning medicinal products authorised purely nationally or in MRP/DCP
Starting from July 6, 2015, the EMA publishes on its website the outcomes of PSUR single assessments and consequent obligations of marketing authorisation holders (MAHs) for active substances or combinations of active substances contained in medicines nationally authorised in the European Union (EU). This initiative aims to support the harmonized implementation of safety measures for medicines with the same active substance across EU Member States.
To support Member States and pharmaceutical companies to implement the outcomes of the assessments, EMA is now publishing the results of these procedures (e.g. revocation, suspension, variation or maintenance of the marketing authorisation) together with the lists of medicines concerned. Furthermore, when the procedure leads to a variation of marketing authorisations, a whole set of information materials is published in all official EU languages: the scientific conclusions, a timetable for implementation of the variation, and where amendments to the product information are required, the wording of the product information.
When a PSUR single assessment procedure leads to a variation of the marketing authorisation, MAHs for products containing the active substance(s) concerned should submit a variation to the relevant national competent authority to align their marketing authorisation with the single assessment outcome (this includes generic medicines or medicines authorised on the basis of well-established use).
Outcomes of PSUR assessments concerning only centrally authorised medicinal products
The Agency already publishes the outcomes of PSUR assessments for centrally authorized medicines, which can be found together with the medicine’s European Public Assessment Report. Furthermore, outcomes of PSUSA procedures are published on the website of the European Commission (Union Register of medicinal products).
Outcomes of PSUR assessments concerning a mixture of centrally and nationally authorised medicinal products
The outcomes of PSUR assessments for both centrally and nationally authorised (mixed) medicines are published in the European Commission Union Register of medicinal products.
Outcomes of informal PSUFU procedures
The outcome of the procedure will be published on the CMDh website. If the outcome includes a recommendation to update the product information, the SmPC and the PL wording to be implemented will also be published, together with the timelines for implementations. The implementation will take place via a type IB variation application under C.I.3.z category. The standard timeline for implementation is within 60 days following publication of the outcome.
Outcomes of informal PSUR work sharing procedures
A few procedures are still ongoing within the frames of the informal EU PSUR work sharing initiative. Outcomes of such procedures, and consequent obligations of MAHs are published on the CMDh website.
National implementation of PSUR assessment outcomes
MAHs should note that outcomes of various PSUR assessment procedures are legally binding, the implementation of which is mandatory. When outcomes are different from revocation or suspension of the marketing authorisation, the Hungarian Agency (OGYÉI) will not send a written call for the MAHs concerning implementation. Therefore, all MAHs are obliged to continuously monitor the websites of the EMA, the Commission and the CMDh for any changes in the marketing authorisations that has to be implemented according to the published timetables, if applicable.
9. Further information
Queries on PSURs may be addressed to OGYÉI via email: email@example.com
The EMA has published a detailed Q&A document on PSURs: Periodic safety update reports: questions and answers