November 2017
CMDh/367/2017 – For public consultation
CMDh Guidance on the Informal Work-Sharing procedure for follow-up for PSUSA for NAPs
Table of contents
1. Problem statement 2
2. Background 2
3. Rationale and prerequisites for Informal WS procedures for PSUSA follow-up for NAPs 3
3.1. Rationale for a developing a new informal WS procedure 3
3.2. Prerequisites for successful informal WS procedures for PSUSA follow-up for NAPs 3
4. Detailed outlines of an informal WS procedure for PSUSA follow-up for NAPs 4
4.1. Applying the informal WS procedure to all PSUSA follow-up for NAPs 4
4.2. Appointment of a Lead MS 4
4.3. Assignment of a procedure number 4
4.4. Submission route and requirements 5
4.5. Mailbox for exchange of AR and comments between MSs 5
4.6. Defined email templates, AR template and MS template for comments 6
4.7. Coordination of the procedure 6
4.8. Timetable for submission, assessment and circulation of the AR and comments 7
4.9. Publication and implementation of the outcome 8
4.10. Commitment of MAHs 8
4.11. Technical details of submission requirements 9
1. Problem statement
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. In these exceptional cases, a Lead MS and/or the PRAC may recommend to the CMDh that a follow-up request is being made to the MAH(s). Where CMDh endorses such a follow-up request, the process for handling of the follow-up should be determined. However, contrary to centrally authorised products (CAPs), no so-called LEG procedure exists for nationally authorised products (NAPs).
As stated in the Joint PRAC/CMDh recommendation paper on the Common understanding on EU PSUR single assessment (EMA/200209/2016), the process for follow-up request on NAPs after PSUSA focusing on appropriate regulatory tools to be used to submit the data for assessment (including early CMDh/PRAC input as appropriate) should be further reflected on.
This Guidance document describes a new procedure to be introduced given the limitations of the existing regulatory tools.
2. Background
As stated in the recommendation paper, follow-up request should be exceptional and if there are any, should be scientifically justified. Also, the regulatory process of the follow-up should be clearly defined in the PSUSA AR (section 6. Other considerations) and this process should be defined in consultation between the CMDh and the PRAC member of the respective Lead MS.
In the recommendation paper, several existing regulatory tools have been identified to handle the follow-up requests:
· worksharing variation;
· signal procedure at PRAC level;
· bringing the next PSUR submission forward;
· initiating an appropriate referral procedure;
However, all these options have their limitations:
· a worksharing variation procedure can only be applied in case only one MAH (or a group of MAHs which are linked, e.g. have concerted practices) is involved;
· a signal procedure should concern a new potentially causal association or a new aspect of a known association but not a safety issue that has been (partly) assessed in a PSUSA;
· with bringing the next PSUR DLP forward resources will be needed to assess the entire PSUR(s), not only the issue that warranted follow-up;
· a referral procedure is normally reserved for a (safety) issue where the interest of the Union is involved.
Given the limitations above and considering the positive experience with the procedure followed during the informal PSUR work sharing (WS) and synchronisation project, an informal WS procedure for the submission and assessment of follow-up after a PSUSA for NAPs has been developed.
Please note that the informal WS procedure for the submission and assessment of follow-up after a PSUSA for NAPs is for exceptional use only and will not be used for issues that could/should have been dealt with and resolved within the PSUSA procedure. Such issues should be dealt within the PSUSA procedure.
3. Rationale and prerequisites for Informal WS procedures for PSUSA follow-up for NAPs
3.1. Rationale for a developing a new informal WS procedure
As mentioned above, all existing regulatory tools have their limitations when it comes to handling of follow-up after a PSUSA procedure for NAPs. This called for a new procedure to optimally handle such requests and to come to a consistent assessment of follow up requests. Since the pharmacovigilance legislation does not provide for such a procedure, a new procedure will therefore be an informal or voluntary one.
When it comes to informal and/or voluntary procedures, extensive experience has been gained with such a procedure in the PSUR WS and synchronisation project. This project showed that the MSs can assess multiple PSUR submissions within one procedure on behalf of the other MSs. The project also showed that, despite the lack of a legal basis, MAHs cooperated in this WS project and implemented the outcome of the scientific assessment performed by the MSs despite the legally non-binding nature of these 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.
An informal WS procedure avoids duplication of work (i.e. parallel assessments by several MSs) and divergent outcomes with subsequent problems at the implementation stage (especially for MRP and DCP products) and will thereby improve consistency across products and MSs.
3.2. Prerequisites for successful informal WS procedures for PSUSA follow-up for NAPs
The lesson learned from the PSUR WS procedure showed that several elements are key to operational success of the informal WS procedures:
· clear description of the issue that warrants follow-up (i.e. LoQ for the MAH(s));
· support and agreement from the MSs;
· cooperation from MAHs via their associations (e.g. EFPIA, Medicines for Europe);
· agreed principles for appointment of a MS performing the assessment of behalf of all MSs;
· clear submission requirements;
· allocation of a unique procedure numbers for easy identification of a procedure;
· default timetables to be applied;
· an assessment report (AR) template in place.
Moreover, the procedure should be eligible for MS request for PRAC advice.
Finally, to ensure cooperation from MAHs, the trade associations will be invited to provide comments via public consultation after the publication of this document.
4. Detailed outlines of an informal WS procedure for PSUSA follow-up for NAPs
For the operational success of the informal WS procedure for PSUSA follow-up for NAPs, several aspects and steps of the procedure are crucial:
1. applying the informal WS procedure to all PSUSA follow-up for NAPs;
2. assignment of a Lead MS;
3. assignment of a procedure number;
4. submission route and requirements;
5. agreement on mailbox for exchange of AR and comments between MSs;
6. defined email templates and AR template;
7. coordination of the procedure;
8. timetable for assessment and agreement on circulation of AR and comments;
9. publication and implementation of the outcome;
10. commitment of MAHs;
11. technical details of submission requirements;
These elements are further detailed in the sections below.
4.1. Applying the informal WS procedure to all PSUSA follow-up for NAPs
When the Lead MS concludes within a PSUSA procedure for NAPs that further follow-up of a certain issue is warranted before the next PSUR and this conclusion is endorsed by PRAC, or if PRAC recommends such follow-up, this will be brought to the attention of the CMDh. If the CMDh endorses the PRAC recommendation for follow-up of a certain issue is warranted before the next PSUR, this follow-up request will be handled via an informal WS procedure. The CMDh has agreed that this procedure applies to all PSUSA follow-up for NAPs.
4.2. Appointment of a Lead MS
When the Lead MS concludes within a PSUSA procedure for NAPs that further follow-up of a certain issue is warranted before the next PSUR and this conclusion is endorsed by PRAC, or if PRAC recommends such follow-up, it is expected that during the PRAC discussion a MS will be identified who would lead on the assessment of the follow-up data. Since the request follows the PSUR assessment, the Lead MS is expected to indicate in the AR (section 6. Other considerations), whether this MS is willing to act as Lead MS for the follow-up procedure. Otherwise, another MS can volunteer to act as Lead MS for the follow-up procedure during the PRAC discussion, or ultimately the CMDh will appoint a Lead MS in its following meeting.
4.3. Assignment of a procedure number
As soon as the CMDh agrees that an informal WS procedure will take place for the assessment of follow-up information after a PSUSA procedure for NAP, the CMDh will issue a unique procedure number; this number will allow MSs to recognise the incoming submissions and associated AR and comments.
The procedure number is built as follows:
MS/H/PSUFU/xxxxxxx/yyyymm
Where:
· MS is the country code of the Lead MS;
· PSUFU stands for PSUSA Follow-Up;
· xxxxxx (6 digits) is the PSUSA number from which the follow-up request originates;
· yyyymm is the DLP of the PSUSA from which the follow-up request originated in year+month format, as reflected in the PSUSA procedure number as well.
This way of constructing the procedure number guarantees unique procedure numbers without the need to maintain a list of previously issued procedure numbers. Furthermore, from this procedure number the PSUSA procedure from which the request originates can be easily identified.
The Lead MS will provide the CMDh secretariat during the meeting where the decision is made with the exact procedure (PSUFU), procedure number, LoQ, timeframe, and to which MAH(s) the request is applicable. The procedure number will be made available to the MAHs via the CMDh Press Release, which is published on the CMDh website, together with the LoQ. The procedure number is used for the submission of documentation by the MAH(s).
4.4. Submission route and requirements
The MAH’s responses to a follow-up request would preferably be submitted via CESP (and in the future via CESSP).
As CESP is not mandatory, the documentation is alternatively submitted to the individual MSs in accordance with their national submission requirements.
Regardless which submission route is used, the submission should be made to all MSs. As PSUSA documents (both PSURs and ARs) are available to all MSs and the follow-up originated from the PSUSA, the proposal would be that submissions are 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. This is not only the case for NAPs, but also CAPs LEG procedures are handled outside the repository.
Finally, the data submitted in relation to the PSUFU should be included in module 5.3.6. of the eCTD.
Technical details and practicalities around of submission are mentioned in section 4.11 of this paper.
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).
4.5. Mailbox for exchange of AR and comments between MSs
The All Human PSUR mailbox ( ) will be used for the exchange of the AR and comments between MSs.
For circulation of the Lead MS’ request for PRAC advice, the PRAC mailbox ( ) should be used with a copy sent to the PRAC secretariat ( ).
4.6. Defined email templates, AR template and MS template for comments
An AR template has been developed for this procedure.
The template contains:
· administrative information;
· tabular overview of the MAHs (and medicinal products) involved with the status of data submission (i.e. submitted/not submitted);
· introduction/background, including the text of the PRAC recommendation/CMDh position that led to the follow-up procedure;
· assessment of MAHs’ responses (subheadings to be introduced by the Lead MS as applicable since various data can be submitted);
· Lead MS’s conclusions;
· RSI (if applicable);
· assessment of MAH’s response to RSI (if applicable);
· MSs comments (if applicable);
· Lead MS’ recommendations regarding:
- product information (if applicable)
- next PSUR (if applicable)
- Risk Management Plan (if applicable)
· a summary for publication, which includes the Lead MS’s recommendation and the rationale/justification for this recommendation.
The template for MS’ comments on PSUSA for NAPs can be used to send comments. An email would be sufficient to state the agreement with the assessment.
For the request for PRAC advice the existing template should be used.
4.7. Coordination of the procedure
The Lead MS will be in charge of conducting and coordinating all aspects of the procedure (i.e. definition of the start of the procedure, circulation of comments, MS’ request for PRAC advice, liaising with the PRAC delegate who represents the Lead MS, etc.).
In case a follow-up request is made after a CAP NAP mixed PSUSA, where the MAH(s) of the CAP(s) would submit their data to EMA in a LEG procedure, the Lead MS will liaise with the EMA Procedure Manager of the LEG procedure to ensure a synchronised start of the CAP procedure and the NAP procedure.
4.8. Timetable for submission, assessment and circulation of the AR and comments
It is envisaged that the PRAC will advise on the most appropriate timelines for submission of the responses by the MAH(s), depending on the seriousness of the issue at hand. The CMDh will consider the PRAC advice and include a submission date in its recommendation.
For the assessment procedure, a default timetable (TT) similar to the one for LEG for CAPs is proposed. This will facilitate the (exceptional) situations where a follow-up request is made after a CAP&NAP mixed PSUSA, where the MAH(s) of the CAP(s) involved would submit their data to the EMA in a LEG procedure.
PRAC advice is to be sought for all follow-up procedures for PSUSA for NAPs. This, as well as the request for a follow-up procedure, will come from PRAC on the basis of a specific safety concern and thus should come back to PRAC to ensure that PRAC retain oversight on the issue. Consequently, the TT should start at defined points in time so that the steps of the procedure will be synchronized with the PRAC and CMDh meeting dates and no unnecessary delay is introduced. To determine the start date of the procedure, the TT for Post-Authorisation Measures (PAMs) assessed by the PRAC which is published on the EMA website can be used (http://www.ema.europa.eu/docs/en_GB/document_library/Other/2015/07/WC500189040.pdf )