Once a medical product is registered in the EU, Periodic Safety Update Reports (PSUR) must be submitted, even if the product is not marketed. These PSURs are prepared at set intervals during the lifetime of the product.
- Periodic Safety Update Reports: General principles
- Submission of PSURs
- BROMI PSURs
- General scope of information in a PSUR
- Frequency of PSUR reporting requirements
- Amendment to the submission cycle
- Sources of information
- FAQs on PSURs
- European PSUR work sharing project
- Products involved in the scheme
- Submission of PSURs under the scheme
- FAQs on EU PSUR synchronisation scheme
Periodic Safety Update Reports: General principles
A PSUR is intended to provide an update of the worldwide safety experience of a medicinal product to Competent Authorities at defined time points post-authorisation. At these times, marketing authorisation (MA) holders are expected to provide succinct summary information together with a critical evaluation of the risk-benefit balance of the product in the light of new or changing information. This evaluation should ascertain whether further investigations need to be carried out and whether changes should be made to the marketing authorisation and product information.
PSURs must be submitted for all registered products regardless of marketing status. A single report may cover all products containing the same active substance(s) licensed by one MA holder.
The report will usually include all dosage forms and formulations, as well as all indications, associated with such an active. Within the PSUR, separate presentations of data for different dosage forms, indications or populations (for example, children vs. adults) may be appropriate, however an overview of the combined data should also be provided.
For combinations of substances which are also registered individually, safety information for the fixed combination may be reported either in a separate PSUR or be included as a separate presentation in the report for one of the separate components, depending on the circumstances. Cross-referencing all relevant PSURs is essential.
Submission of PSURs
Periodic Safety Update Reports should be submitted with the following files.
- Covering letter (which should contain a summary of the submission being made Product License number, the product name, the PSUR reporting period)
- Application form (which must contain all of the relevant details such as the PL number, MR procedure number (if relevant), the contact person details and the period of the PSUR)
- PSUR (supplied in Adobe *.pdf format and ideally less than 20MB)
For CD based applications: Any supplied CD’s must clearly contain the PL number on view, without any sticky labels to prevent the CD’s getting stuck in the CD drive.
Products containing the same active substance(s) and of similar work types may be bulked by one MA holder subject to the work types being kept consistent (ie submitting National separately, CMS separately and RMS separately). PSUR's submitted must not mix different work types into the same notification.
PSURs can be submitted via the portal but please ensure that the general submissions form is used. Please note that on submission through the portal a confirmation email with an eight digit reference number should be received. If you do not receive this information then your submission has not been received by us and you should resubmit the application.
Following submission of your PSUR an acknowledgement letter will be sent, if you do not receive this within 14 days then you should contact the Regulatory Information Service (RIS) to ensure we have received the application.
Following a successful BROMI pilot a new self certification scheme for PSURs is available. Self certification will only apply to purely national authorisations (i.e. products authorised through MRP and DCP will be excluded) of well established medicines. For the purpose of self-certification of national PSURs well established medicines are defined as actives which have been internationally approved for more than 15 years, do not have black triangle and the safety profile is well known.
If all the criteria (see below) apply the self certification can be submitted. Some spontaneous reports may have been received during the reporting period however these may not represent a new safety signal. Therefore in these circumstances these PSURs could be self-certified.
1.The active is well established.
2.There are no ongoing safety issues.
3.The product information is up to date or a variation to update in line with brand leader will be submitted within three months.
4.The product is not part of the EU PSUR work sharing scheme.
5.There is no Risk Management Plan for the product.
6.No signals have been generated as result of information in the PSUR.
A PSUR application should be submitted according to the usual routes. Please clearly state in the reason comment that it is a BROMI PSUR. The completed letter template should then be submitted in place of the PSUR.
General scope of information in a PSUR
All relevant clinical and non-clinical safety data should cover only the period of the report (interval data) with the exception of authorisation status information for initial and renewal applications, and data on serious, unlisted adverse reactions. These should be provided for both the period in question and as cumulative summary tabulations starting from the International Birth Date (IBD).
The main focus of the report should be adverse reactions. Unless indicated otherwise by the reporting health-care professional, all adverse experiences reported spontaneously should be considered adverse reactions; for clinical study and literature cases, only those judged not related to the medicinal product by both the reporter and the MA holder should be excluded.
The PSUR should include a scientific evaluation of the risk: benefit balance of the product(s), and should be generated according to the ICH E2C guidelines.
Addendum to ICH E2C: Clinical Safety Data Management (external link)
Frequency of PSUR reporting requirements
PSURs should be submitted at the following times from the time of authorisation, for all medicinal products unless the marketing authorisation makes different provisions:
- Immediately upon request
- At least 6 monthly after authorisation and until the placing on the market
- At least 6 monthly for the first two years after being placed on the market
- Annually for the subsequent two years
- Thereafter at three-yearly intervals
Multiples of six-monthly PSURs are acceptable, provided that the MA holder submits a PSUR bridging summary report (BSR). Where multiple reports are being provided the BSR should be comprehensive.
The data lock point (DLP) is defined as the cut-off date for data to be included in a PSUR. It may be set according to the European birth date (EBD) or IBD of the medicinal product. The MAH should in any case submit the PSUR no later than 60 days after the DLP. For generic products the DLP may be set according the EU harmonised birth date (EU HBD) of a medicinal product as published on the Heads of Agencies (HMA) website (external link). Further details of this scheme are provided below.
Each PSUR should cover the period of time since the last update report. A PSUR, and BSR if appropriate, should also be submitted at renewal in line with renewal guidelines. Reports previously submitted for each marketing authorisation do not need to be resubmitted and duplicate reports should not be submitted.
The table below shows the PSUR submissions for a product that is marketed immediately after approval. If the product is not marketed at approval then there will be extra six monthly PSURs before marketing.
Time covered by PSUR
8, 9 etc.
Please note the renewal is no longer part of the actual PSUR cycle. The PSUR cycle continues regardless of any communication from competent authorities, therefore you should maintain your PSUR cycle.
Amendment to the submission cycle
Section 6.2.4.c ‘Circumstances where the Submission Cycle may be Amended’ states that in certain circumstances the frequency of PSURs may be increased (if there is a specific safety concern) or decreased.
There is European agreement that the PSUR cycle for generic products may move directly to the three-yearly cycle in line with the brand leader rather than start with six-monthly PSURs, unless potential safety issues that may require monitoring are identified in the Safety Assessment included within the registration dossier.
The request to amend the PSUR cycle should be included in the registration dossier and supported in the Safety Assessment. This will be agreed as part of the MA approval. If a request to amend the PSUR cycle is not received then the PSUR cycle will default back to 6 monthly reports for two years, annually for two years and then every three years thereafter.
Once authorised the PSUR cycle may be altered by means of a type II variation and this would be associated with the appropriate fee. The application must be accompanied by a suitable justification for amending the cycle. If the PSUR cycle is to be amended in line with the innovator product according to the EU HBD and DLP for PSURs, as published on the HMA website, then a notification is required which will not attract a fee (see European work sharing project below).
All PSURs are assessed by the MHRA and if specific safety issues emerge for individual products the authorisation holders may be requested to submit more frequent PSURs than once every three years, if this is believed to be of benefit to the assessment/monitoring of the safety issue.
Sources of information
Generally data from the following sources of adverse reaction case information are potentially available to a MA holder and should be included in the PSUR:
1. Direct reports to authorisation holder (or under MAH control):
- spontaneous notifications from health-care professionals
- MA holder sponsored clinical studies or named patient (compassionate) use
- spontaneous notifications from consumers/patient
3. ADR reporting systems of regulatory authorities:
- spontaneous notifications and non-spontaneous notification
4. Other sources of data:
- reports of adverse reactions exchanged between contractual partners (e.g. licensors-licensees)
- data in special registries, such as maintained in organ toxicity monitoring centres
- reports created by poison control centres
- epidemiological databases
FAQ on PSURs
- Are minor editorial changes permitted to the SPC at the time of PSUR submission (which are not related to the reference safety information) without the requirement for a variation, particularly to bring it in line with the SPC guideline? (For example to include 'For full list of excipients, see section 6.1.' and 'not all pack sizes may be marketed')
No, the processing of a PSUR application does not allow for changes to the SPC. Changes to SPC must be made by variation or exceptionally at renewal.
- Does the data lock point that is set to capture the 3 year period have to run for 3 years to the day, or is there some flexibility?
There is some flexibility as long as the period does not extend past 3 years. Remember this is 3 years from your last DLP and not from the date of grant of renewal/acceptance of PSUR. Please also see Q 14 from Q+A document on HMA website (external link).
- Can PSURs be submitted via the Sentinel portal?
PSURs maybe submitted via the portal (size permitting) and these submissions should be made using the General Submissions Form accompanied with a cover letter.
- Should we be requesting drug analysis prints (DAPs) and product analysis prints (PAPs) from theMHRA when preparing our PSUR?
DAPs and PAPs can be requested if the MAH feels the information will be useful to your risk: benefit assessment. However it must be remembered that it is the MAH who has the responsibility to collect the appropriate data.
- We have received several Anonymised Single Patient Reports (ASPRs). How do we include these in the PSUR? Should they be in the line listings?
On receiving an ASPR it is the MA holder’s responsibility to check the report and include it in their database. Once included in the database these should then be used in the same way as spontaneous or literature reports when preparing the PSUR.
- If I apply for an Abridged application what PSUR cycle should I follow?
Once granted an abridged application is a new marketing authorisation and therefore the standard cycle will apply unless you apply for a waiver to move straight to a three year cycle. The waiver can be applied for when a generic product contains a well known active which has no pharmacovigilance issues or risk management plans in place. Where the active is on the list of EU harmonised data lock points (DLPs) then you are strongly encouraged to follow these dates. The renewal should be submitted with the most convenient DLP
NB a renewal will still be required even if the originator MA has been renewed.
- Does a change of ownership application restart the PSUR cycle?
No. The cycle should remain as previously agreed. If you take ownership of an MA prior to renewal it is important you ascertain whether the previous MA holder had obtained a waiver and when the next PSUR is due. If the original MA is national and has been renewed previously then a further renewal is not required
European PSUR work sharing project
Under the auspices of the Heads of Agencies (HMA) a large work-sharing project is underway. Innovator companies were asked to propose dates for substances for which they considered their product to be the originator, and this was used as a basis for compiling a list of European harmonised birth dates (EU HBD) and data-lock points (DLPs) for active substances. This list has now been adopted by all national agencies and is published on the HMA website http://heads.medagencies.org (external link) together with further details regarding the scheme.
Under the scheme all products involving the same active substance will have the same EU HBD and DLP and therefore the same PSUR submission cycle. This will allow sharing of the PSUR assessment work load across the EU. Each active substance will be allocated a P-RMS (Reference Member State for the PSUR) who will take the lead in the assessment. For mutually authorised licences the P-RMS and RMS may not be the same EU member state.
The HMA envisages that the benefits of the project are:
- MA holders of original medicinal products only have to prepare a single PSUR for the concerned products which can be simultaneously submitted to all EU Member States.
- MA holders of generic medicinal products have the same advantages as above, and can eventually compile joint PSURs and thereby mutually share the workload.
- The regulatory authorities will be able to mutually share the assessment tasks of the PSURs, thus preventing duplicate assessment work.
Products involved in the scheme
The scheme is voluntary but MA holders for all products with the same active substance will be encouraged to submit PSURs according to the published dates. MA holders for generic products will be encouraged to submit PSURs to all member states where the product is authorised according to the published dates but will be given a year from publication to implement the HBDs (and DLPs). In the meantime PSUR submission for generics should be according to existing cycles. It is therefore advantageous to adopt HBDs as soon as possible. Where the published HBDs are adopted there will be no need to apply by variation to amend the PSUR submission cycle.
An additional list of EU harmonised birth dates and data lock points has recently been published on the Heads of Agencies website (http://www.hma.eu/80.html (external link)).
Herbals, homeopathics and biologicals such as vaccines and blood products are excluded from the scheme at present.
Submission of PSURs under the scheme
PSURs should be submitted within 60 days of the adopted DLP according to national requirements. The UK prefers electronic submissions. Please submit PSURs according to UK guidance in Special MAIL 5.
A cover letter (template available at http://www.hma.eu/80.htm (external link)) should be supplied with the PSUR and this should include:
- (i) A statement that the PSUR is being submitted under the PSUR work-sharing project on assessment of PSURs
- (ii) The Procedure Number (can be retrieved from the list of HBDs, DLPs and P-RMSs on http://www.hma.eu/80.htm (external link))
- (iii) Confirmation that the PSUR will be submitted in all Member States where products containing the active ingredient are authorised
- (iv) A single contact point (including an e-mail address) for communications regarding submissions under the scheme.
A table in Word format should be annexed to the cover letter which contains information on:
- a. in which Member States the relevant product is authorised
- b. name of the Marketing Authorisation holder
- c. under which product name, pharmaceutical form and strength
- d. the Marketing Authorisation number along with MRP/DCP procedure numbers where applicable.
If the relevant product is not authorised in the P-RMS a copy of the table should also be sent to the P-RMS with a specific cover letter (see template on HMA website (external link)).
Where the UK is P-RMS copies of cover letters should be sent to the PVS mailbox(email@example.com)
Enquiries regarding PSUR assessment and amendment of PSUR cycles can be e-mailed to: firstname.lastname@example.org.
General enquiries regarding the formatting of PSURs submissions should be sent to Mr Matthew Hillier (email@example.com) or Mr Shaun Fiddes (firstname.lastname@example.org) as detailed in Special MAIL 5.
FAQs on EU PSUR synchronisation scheme
- How do I amend my PSUR cycle in line with the EU harmonised birth date and DLP?
The CMD(h) has agreed that no variation is required to implement the new EU DLPs. Previous guidance from the MHRA had indicated that a notification would be required. In clarification of this advice notification in the cover letter of the PSUR will be accepted as notification of intent to follow the harmonised DLPs.
Companies are reminded that it is their responsibility to ensure that there are no gaps in the data provided.
- When do I need to submit a type II variation to amend my PSUR cycle?
You will need to submit a type II variation if you wish to harmonise the dates of a range of products containing the same active ingredient with a company specific international birth date which is not on the list of harmonised birth dates on the Heads of Agencies web site. A Type II variation is also required if you wish to reduce the frequency of the PSUR submission (e.g. if a waiver on 6 monthly PSURs was not applied for on granting of the marketing authorisation of a generic product) if you are not using the EU harmonised DLPs and cycles.
- My product is on the list but the harmonised DLP is shortly after my next submission is due. When should I join the scheme?
You can start the scheme at any point. If the harmonised DLP is shortly after your required submission you should submit your PSUR as required ensuring that you notify of your intent to participate in the scheme. An update then should be supplied either in the form of line listings or addendum report as appropriate. If you are unsure of the best approach or the suitability of an addendum report please check with the Therapeutic Reviews Group before making your submission. If the product is marketed in other Member States their agreement on your course of action should also be obtained from the relevant competent authorities.
- Do I submit my PSUR produced with the harmonised birth date only to the MHRA?If you only have a marketing authorisation in the UK then you only need to submit your PSUR to the MHRA. The submission should be made in line with Special MAIL 5. If you have marketing authorisations in other member states for that active even if the product name is different you should submit the same PSUR to those Member States. You should check requirements for notification with individual competent authorities. A copy of the cover letter should be sent to the P-RMS.
- I am participating in the scheme and the UK is P-RMS for my procedure but we do not an authorisation in the UK. Where do I send the cover letter?
A copy of the cover letter should be sent to the PVS mailbox (email@example.com)