This page is intended to provide advice to Marketing Authorisation Holders of centrally authorised medicinal products about procedural and regulatory aspects to the Risk Management Plan (RMP) lifecycle during the post authorisation phase. It addresses the classification of changes to the RMP, submission requirements and aspects to be considered in the management of parallel procedures affecting RMP. Revised topics are marked 'New' or 'Rev.' upon publication.
A PDF version of the entire post-authorisation guidance is available:
- European Medicines Agency post-authorisation procedural advice for users of the centralised procedure
- European Medicines Agency post-authorisation procedural advice for users of the centralised procedure (with track changes)
It should be read in conjunction with the Guideline on good pharmacovigilance practices – Module V – Risk Management Systems (Rev 1) and the European Commission 'Variations Guidelines’ 2013/C 223/01.
MAHs must in all cases comply with the requirements of Community legislation. Provisions that extend to Iceland, Liechtenstein and Norway by virtue of the European Economic Area agreement are outlined in the relevant sections of the text.
- 1. When should I submit a new/updated RMP? NEW June 2016
A new RMP or an update of the RMP, as applicable, may need to be submitted at any time during a product’s lifecycle, including the post-authorisation phase.
Since July 2012, all new marketing authorisations (MAs) should include an RMP. However, as the provision of an RMP was not mandatory before that date, there are still MAs for some centrally authorised products without an RMP. It should be noted, however, that there are situations (e.g. in view of new safety concerns, significant changes to the MA) that may trigger the need to introduce an RMP during the product’s lifecycle.
Whenever new data are provided as part of a regulatory application in the post-authorisation setting, the MAH should consider whether consequential changes to the RMP are needed. Should this be the case, a revised RMP version should be included as part of the regulatory application as it is the responsibility of the MAH to update the RMP whenever new information is being received that have an impact on the content of the RMP.
An updated RMP should always be submitted if there is a significant change to the safety information/ safety profile of one or more medicinal products included in the RMP.
A new RMP or an RMP update will normally be expected to be included in the following situations:
- with an application involving a significant change to an existing marketing authorisation:
- significant change in indication;
A significant change in indication is a change of authorised indication(s) of a medicinal product where the new treatment target population differs from the one for which the medicinal product was previously authorised. This includes (but is not limited to) a new disease area, a new age group (e.g. paediatric indication) or a move between different stages or severities of a disease.It may also include a move to an earlier or later line of therapy or a change to the concomitant medication specified in the indication.
- new dosage form;
- new route of administration;
- new manufacturing process of a biotechnologically-derived product.
- at the request of the Agency or national competent authority or proactively by the MAH when there is a concern about a risk or a decreased benefit affecting the benefit-risk balance;
- with a submission of final study results with a consequentialimpact on the RMP;
- with the renewal application;
- in the event of other clinicallyimportantchangestotheproductinformation e.g. new or major amendment of existing contraindication;
- with a PSUR for a single centrally authorised medicinal product (CAP), when changes to the RMP are a direct result of data presented in the PSUR.
RMP updates cannot be accepted together with the PSUR EU single assessment (PSUSA) of medicinal products where the procedure includes several CAPs which are not part of the same global marketing authorisation (N.B. duplicate CAPs (same INN, same MAH) are acceptable) and/or nationally authorised products. In this case, MAHs should update their RMP through another upcoming regulatory procedure affecting the RMP or alternatively, through a separate variation which can be submitted after finalisation of the PSUR single assessment procedure (see also Question 2 below).
In addition to the examples above there are other situations when an RMP update may be warranted. The need for an update to the RMP, including procedural aspects, should be discussed with the Agency, as appropriate, well in advance of the submission of an application, and in particular when involving a significant change to an existing marketing authorisation and/or parallel procedures warranting an RMP update.
- with an application involving a significant change to an existing marketing authorisation:
- 2. When is my RMP a stand-alone variation? NEW June 2016
It is expected that for RMP updates which are consequential to the data provided in an application, the updated RMP should be provided as part of the same application (see also Question 4 below). However, if an RMP needs to be updated outside any regulatory procedure, this RMP should be submitted as a stand-alone variation.
A stand-alone variation for updates of the RMP may be foreseen or requested by the Agency in particular in the following situations:
- In case of changes to the safety concerns outside another procedure; for instance, if interim results of a study assessed as a post-authorisation measure (PAM) lead to changes in the safety specifications (i.e. the need to add, delete or reclassify safety concerns);
- As a follow-up of a PSUR procedure.
RMP updates cannot be accepted together with the PSURs of medicinal products (centrally and/or nationally authorised) subject to a PSUR EU single assessment (PSUSA), unless the PSUSA procedure includes only CAPs which are part of the same global MA (e.g. duplicate MAs). MAHs should update their RMP through another upcoming procedure affecting the RMP or alternatively, through a separate variation which can be submitted after finalisation of the PSUSA procedure;
- In case of proposed changes to already previously agreed category 3 studies in Part III.4.3 of the RMP. This applies also when the MAH has provided an updated / amended protocol that has been assessed via the PAM procedure and which has an impact on the description of the study in Part III.4.3.
- 3. What if my application does not include an updated RMP? NEW June 2016
If the MAH considers that no update of the RMP is warranted at the time of submission of a regulatory application (e.g. major type II variation, line extension), this should be duly justified in the application. Such justification should preferably be part of the cover letter and the (non)clinical overview (addendum). Following the assessment of the application and the RMP justification provided by the MAH, the PRAC/CHMP may or may not agree with the view that no RMP changes are warranted. If not agreed, the MAH will be requested to provide an updated RMP in response to a CHMP Request for Supplementary Information (RSI) during the procedure.
In principle, it is essential to always strive to conclude the RMP assessment and to update the RMP during the procedure i.e. a final updated RMP version should be provided for agreement prior to the CHMP Opinion. However, if the PRAC/CHMP agrees that the requested update may not be possible during the procedure taking the procedural timelines into account and only relatively minor RMP changes are warranted, the RMP can instead be updated at the ‘next regulatory opportunity’, i.e. as part of the next application resulting in more substantial changes to the RMP. In this case, unless requested by PRAC/CHMP, there is no requirement to submit an immediate variation in order to update the RMP following the finalisation of the procedure.
In the event that relatively minor RMP changes are requested by PRAC/CHMP for implementation at the ‘next regulatory opportunity’, the changes can be included as part of another appropriate regulatory procedure under a single scope (e.g. as part of a type IB variation or type II variation affecting the RMP without the need for an additional specific variation(s)) (see also Question 5 below). However, in the situation where additional data and significant further assessment is still necessary, this constitutes a separate type II variation scope which means that a specific variation is still required regardless of whether it is submitted as a stand-alone variation application or part of a grouped application.
- 4. Which variation classification will apply for my RMP updates? NEW June 2016
4.1. Consequential RMP updates
All RMP changes are in principle changes to the Marketing Authorisation and therefore require the submission of a specific variation. However, when the RMP updates are consequential to the data provided in an application, the updated RMP should be included as part of the same application. The latter is frequent for type II variations submitted under categories C.I.4 or C.I.6 when the product information is affected, type II variations under category C.I.13 when a final study report is provided without any impact on the product information, for line extension applications, renewals and for PSURs when the proposed update is related to the data submitted in the PSUR application.
In addition, in case changes to the conditions (such as study objective, due date) to the MA as described in Annex II D (i.e. obligations) and Annex II E (i.e. specific obligations) of the product information are implemented as part of a type II variation under category C.I.11.b, and/or changes to additional risk minimisation measures in Annex II D (such as the key elements of educational material), MAHs should also implement consequential changes to the RMP as part of the same application.
4.2. Variation classification categories for stand-alone RMP updates
Type II C.I.11.b
- Introduction of a new RMP outside another regulatory procedure.
- Addition, modification or deletion of safety concerns (identified risks, potential risks, missing information) not previously assessed and agreed by the PRAC/CHMP (e.g. with signals, PSURs).
- Changes to agreed category 3 post-authorisation studies in the RMP (MEAs), if there is an impact on the description of the study (objectives as given in section III.4.3 of the RMP in the new format excluding changes to due dates) and/or to risk minimisation measures in the RMP not previously assessed and agreed by the PRAC/CHMP;
- Study objective: e.g. no more hypothesis testing.
- Study population: type or number, if it may restrict the objective; e.g. considerable sample size reduction; decrease in centres or geographical spread.
- Study design: e.g. follow-up type; passive versus patient diary.
Type IB category C.I.11.z
- Updates of RMPs not falling within the scope of type II variations (see above) are in principle type IB variations.
- Addition, modification or deletion of a safety concern (identified risks, potential risks, missing information) which has already been assessed and requested by the PRAC/CHMP in a previous procedure; i.e. the changes have already been formally assessed and agreed in principle as part of a previous procedure (e.g. assessment of signals, PSURs, variations, PAMs) by the PRAC/CHMP, although the agreement on the exact wording to be implemented in the RMP is still pending and further assessment is therefore required.
Note: In order for the implementation of pre-agreed RMP changes to be handled as a type IB variation, no additional data should be needed or submitted to support the proposes changes.
- Change to the final due date i.e. the date for the provision of the final study report for category 1, 2 or 3 studies in the RMP and/or the Annex II, as relevant.
Note: Because no specific changes are identified by the variations classification guideline as falling by default into the type IB variation category, the above changes lead to such variation only when they constitute the reason for submitting the updated RMP. In case the MAH takes the opportunity to propose such changes with an RMP update undertaken for another reason (e.g. as part of a type II variation), these changes are accepted as minor and do not trigger additional variation scopes (please refer to Question 5 below).
Type IAIN category C.I.11 a)
- Implementation of changes to the conditions based on an exact wording agreed by PRAC/CHMP without any further changes, provided that no linguistic review of translations is required in case of simultaneous changes to the Annex II (i.e. deletion of information, changes to timelines are acceptable but not the implementation of new wording as such).
- Update of the RMP in response to a request following signal detection provided an exact wording agreed by PRAC/CHMP is implemented without further changes.
- Update of the RMP in response to a request following assessment of a protocol of a category 3 study provided an exact wording agreed by PRAC/CHMP is implemented without further changes.
Note:The changes to be implemented must already have been assessed by the Committee(s) in a previously concluded procedure; only the exact agreed wording is implemented, no additional changes are proposed and no further assessment is required.
However, it should be noted that it is rare that an exact wording is pre-agreed and therefore in most cases a type IB or type II variation will be required. Regardless, the MAH should always specify in the submission whether or not the proposed changes have already been assessed, and if so, as part of which procedure.
- 5. Which changes can be included in an RMP update without the need for an additional variation? NEW June 2016
It is in principle acceptable to take the opportunity of a regulatory application (e.g. a type IB or type II variation) which warrants an update of the RMP to implement also:
- minor administrative changes to the RMP;
- template-related updates;
- updates of clinical / post-marketing data in line with a new data lock point (DLP) (e.g. exposure data and data coming from clinical trials without impact on key safety information or final due dates);
- changes to category 4 studies listed in table III.4.4 (stated additional pharmacovigilance activities, also known as ‘REC’= Recommendation);
as long as the proposed changes are not affecting the identified and potential risks, the summary of the safety concerns, the pharmacovigilance plan, the risk minimisation measures or any existing post-authorisation efficacy study (PAES).
Further, in the event that relatively minor RMP changes are requested by PRAC/CHMP for implementation at the ‘next regulatory opportunity’, i.e. as part of the next application resulting in more substantial changes to the RMP (e.g. type IB variation, type II variation, line extension, renewal), these changes can be included as part of the next upcoming RMP update under a single scope i.e. without any need for an additional specific variation, unless there is a defined timeframe by when the update is requested and there is no other planned major RMP update in the same timeframe. However, it should be noted that in general an additional type II variation for the requested RMP update is required whenever there is a need for further substantial PRAC/CHMP assessment (i.e. when additional data and/or justifications are provided).
A change to the final due date i.e. the provision of the final study report for category 1, 2 or 3 studies in the RMP can be included as part of another type IB variation affecting the RMP or type II variation resulting in substantial changes to the RMP without the need for an additional scope i.e. any additional specific type IB variation. Further, if an updated protocol/summary of protocol (annexed to RMP) has been assessed and agreed as part of a post-authorisation measure (PAM) procedure, the agreed updated protocol can thereafter be included in RMP Annex 8 at the ‘next regulatory opportunity’ (e.g. a type IB or type II variation) without any need for a specific variation.
- 6. Can I group my RMP updates? NEW June 2016
Each proposed ‘major change’ to the RMP triggers in principle its own type II variation scope.It should be noted that one specific type II variation is required for each scope also when submitted together with other major changes as part of a grouped variation application. The same rules apply to the grouping of major RMP changes as to the grouping of any other (non)clinical type II variations:
- changes meaningful to be reviewed simultaneously can be grouped;
- non-clinical and clinical safety changes are not accepted as part of the same grouping;
- and grouping should not delay the implementation of important changes (for instance a proposed extension of indication should not be grouped with safety variations).
With regard to multiple ‘minor changes’ which can be assessed as type IB variations if submitted on their own, these do not require a grouped application even when submitted together; instead it is acceptable to include these minor changes as part of one single type IB variation or type II variation without the triggering of additional type IB variation scopes i.e. any need for additional variations (see also Question 5 above).
The following cases are meant to exemplify how these rules would be applied for RMP updates:
Addition of a new Adverse Drug Reaction and a relevant warning to the SmPC via a type II variation C.I.4 with consequential update of the list of important identified risks in the RMP and submission of a final study report for a category 3 study in the RMP via a type II variation C.I.13 with consequential updates of the RMP. This can be submitted as a grouped application of 2 type II variations.
Submission of a final study report for a category 3 study via a type II variation C.I.13 with consequential updates of the RMP, and:
- Deletion of the category 3 study in the RMP – no need for separate variation since related to the main application;
- Addition of a safety concern in the RMP following a request from PRAC as part of a PSUR assessment – 1 (grouped) Type II category C.I.11.b if additional data are submitted and/or further significant assessment is required; no need for a separate variation otherwise as the change is implemented as part of a type II variation affecting the RMP;
- Changes to the due date for the provision of the final study report for a category 3 study in the RMP – no need for a separate variation as the change is implemented as part of a type II variation affecting the RMP;
- Update of the RMP with new data on the clinical trial exposure – can be implemented within the variation without the need for an additional variation.
Changes to the due date for the provision of the final study report for two category 3 studies in the RMP.
This can be submitted as a single type IB variation under category C.I.11.z; no grouping necessary.
On the other hand, a grouped application is generally not acceptable if it creates the risk of postponing the implementation of important safety information in the RMP:
- e.g. in case a type II variation is submitted under category C.I.6 (Extension of Indication), the RMP version submitted as part of this application should include only changes that are consequential to the new data provided and the new proposed indication.As the procedure for an extension of indication application may take some months to finalise, other non-related changes should as a principle not be included and/or grouped with an extension of indication application as the implementation of safety information should not be delayed.
- 7. How should I handle parallel RMP submissions? NEW June 2016
It is in general acceptable for MAHs to submit an application affecting the RMP whilst (an)other procedure(s) which involves the assessment of an updated RMP is already ongoing (i.e. over-lapping RMP assessments).
There are two alternative approaches to the handling of different RMP versions for which the assessment is over-lapping, and the MAH should choose the option that facilitates the assessment the most.
Whenever separate applications affecting the RMP are submitted in parallel, in order to facilitate the review, it is generally agreed that the MAH initially and whenever appropriate during the procedure submits one joint RMP version as a ‘working document’. This single updated RMP version can include the scopes of the parallel variation applications affecting the RMP. However, the proposed changes should be highlighted with different colours in order to ensure that the specific changes related to one application can easily be distinguished from the changes of the other(s).
In case the parallel applications reach the CHMP opinion at the same time, the consolidated RMP version will be adopted by the Committee. However, it should be noted that in case the applications do not reach the opinion-stage at the same time, at the time of the first opinion the MAH will need to provide a final RMP version with a new version number including only the agreed changes related to the scope of the variation application for which the CHMP is about to adopt an opinion. Thus, the joint ‘working document’ RMP may need to be split at a certain point in time during the procedure and procedure-specific RMP versions provided.
Alternatively, it might be more appropriate when parallel procedures will follow very different assessment timetables to opt for an approach identical to the handling of the parallel over-lapping assessment of different versions of the product information; the RMP submitted with each procedure should only include the changes related to that procedure:
- e.g. a new version of the RMP updated as requested by PRAC following the PSUSA procedure is submitted as a type IB variation C.I.11.z. This RMP version should include only the changes related to the PSUSA procedure.
- Further, an updated RMP version is provided as part of a type II variation C.I.6 (extension of indication). This RMP version should only include the changes that are consequential to the extension of indication (and not the changes related to the PSUSA procedure).
- Once the type IB variation has been approved, the MAH can submit a consolidated RMP version. The best way forward procedurally is generally to submit an updated RMP version as part of the MAH’s responses to an RSI for the extension of indication. This RMP version can include the changes that have been approved as part of the recent type IB variation as clean text as well as the changes related to the extension of indication with track changes.
Regardless of the approach chosen, the MAH should always provide a clear description of the scope(s) of the submission in the cover letter and the changes implemented in the RMP including references to related (previous/parallel) regulatory procedure(s) (see also Question 8 below).
- 8. How shall I present my RMP update? NEW June 2016
Guidance on the format and content of the RMP as outlined in GVP module V and RMP template has been made available in the Pharmacovigilance section of the Agency’s website. The submitted RMP should follow the RMP template and guidance.
The RMP should be provided in CTD section 1.8.2. RMP versions submitted for assessment should be version controlled and dated. All parts and modules of the RMP should be submitted in one single PDF-file so that a complete RMP is provided to the Agency.
Only clean versions of documents in PDF format should be managed within the eCTD lifecycle. However, due to the fact that additional formats are required to facilitate the assessment i.e. ‘tracked changes’ versions for SmPCs, RMPs or other documents as specified by the agency, these should be provided in Word format in the separate folder ‘XXXX-working documents’. Further details in this regard can be found in section 2.9.9 of the TIGes Harmonised Guidance for eCTD Submissions in the EU. Although the approved RMP = One integral document (i.e. one pdf with all parts/modules/annexes), it is generally not necessary to include the RMP annexes as part of the ‘working document’ version (unless any of the annexes are actually revised).
In general, any submitted version of the RMP should be based on the latest approved version (i.e. the latest version agreed by CHMP). However, sometimes it may be more appropriate to base the next version to be submitted on the latest RMP ‘working document’ version, especially when several procedures affecting the RMP are ongoing in parallel (see Question 7 above).
Regardless, the submitted RMP version should be seen as a draft, until approved. Details of the RMP approval status should be provided in the Module I of the document. The revised RMP should always get a new version number every time an updated RMP version is approved.
If two or more draft RMPs are under evaluation in the context of overlapping procedures (e.g. an RMP update is submitted before the assessment of the RMP previously submitted in the context of another procedure is concluded), at the time of the CHMP opinion for the procedure that is finalised last, the MAH should ensure that the approved RMP version includes all the amendments approved in the draft RMPs previously assessed (i.e. a consolidated version should be provided).
Companies are strongly encouraged to streamline RMP amendments and submissions, in co-operation with the EMA (or Reference Member State for non-CAPs), in order to facilitate RMP assessments throughout the product’s life-cycle.
In the event that the RMP update, following a request(s) by PRAC/CHMP, includes changes originating from previous regulatory procedures, the highlighted ‘working document’ version should include as an inserted comment for each proposed change a reference to the procedure number of the originating prior procedure/assessment. Sometimes it may also be helpful to provide such overview in a tabular format. (For further guidance regarding the handling of different parallel applications affecting the RMP, please refer to Question 7 above.)
When relevant, a discussion of the proposed RMP changes should be included in the (non-) clinical overview (addendum). It should be noted that the provision of a (non-)clinical overview (addendum) is mandatory as part of a (non-)clinical type II variation application which includes a revised RMP regardless of the fact that there may be no impact on the product information. In this case the (non-) clinical overview (addendum) should discuss and justify the proposed RMP changes. On the other hand, a (non-) clinical overview (addendum) is never required as part of type IA and type IB variation applications.
In the EU application form (AF) and for (non-)clinical variations, the “Present/Proposed” table will in general only reflect proposed changes to the EN Annexes (SmPC, Annex II, labelling and Package Leaflet). It is not foreseen that the updates to the RMP are reflected in the AF in detail unless quite limited in scope. Instead, when comprehensive changes to the RMP are proposed, it is recommended to provide a comparative table of the RMP (latest agreed version vs. proposed version), summarising – for all individual RMP parts and modules – the main updates. For example, all changes linked to the implementation of a new template can be summarised as ‘new RMP template’. Such comparative table should be provided as an annex to the AF.
- 9. Can I submit a version of the RMP after the Opinion to reflect the last minute changes made during the CHMP? NEW June 2016
As a matter of principle the day of the CHMP Opinion/EMA Notification is the last opportunity for the MAH to provide an updated version of the RMP (in word format) for agreement. The same RMP version with the same version number – without any additional changes - can thereafter be submitted as part of a formal eCTD closing sequence post-opinion. However, if additional changes to the RMP are identified post-opinion after receipt of the document, an updated RMP version with a new version number should be provided for review as part of a type IB variation under category C.I.11.z.
The same principles apply also in situations when there are different RMP versions undergoing assessment in parallel and there is a need to provide a consolidated RMP version which will include all agreed changes to the RMP (see also Question 7 above). In general, MAHs are requested to provide the final consolidated RMP version (in word format) before the date of the CHMP Opinion/EMA Notification. If this is not possible, the MAH may submit the final consolidated version post-opinion. In such instance, the final consolidated RMP should be submitted as a type IB variation under category C.I.11.z. but not as part of a closing eCTD sequence post-opinion since there is a need to review it.
- 10. When should study progress reports be submitted? NEW June 2016
The timelines of the progress reports for a given study should be pre-specified and indicated in the protocol. These progress reports may include available interim results, but there is in general no obligation or recommendation to include interim results in PSURs and RMPs unless required as part of an agreed pharmacovigilance plan. This is without prejudice that a variation as appropriate should be submitted should these interim results lead to product information changes or RMP changes.
- 11. Is the PRAC Rapporteur involved in the assessment of RMP updates? NEW June 2016
The PRAC Rapporteur will be involved in the assessment of all variations that include an updated RMP. For type IB variation including RMP, PRAC Rapporteur will be in the lead of the assessment. For type II variations, the CHMP or PRAC may take the lead during the assessment depending on the composition of the data provided, and this will be decided on a case-by-case basis at the time of the EMA validation.
Similarly, on a case-by-case basis, the PRAC Rapporteur may also later become involved in the assessment of an application if requested by the CHMP during the procedure.
At the time of validation the Agency will inform the MAH of the involvement of the PRAC Rapporteur through the assessment timetable which will refer to the relevant assessment reports expected from the PRAC Rapporteur, as appropriate.
- 12. How long after the European Commission decision should Annex 1 of the RMP be submitted to EudraVigilance? NEW June 2016
If an immediate Commission Decision is applicable, there is a period of 30 days after the Commission Decision to submit the Annex 1 of the RMP to EudraVigilance. If no immediate Commission Decision applies, the MAH should submit the Annex 1 within 30 days of the CHMP Opinion.
- Directive 2001/83/EC
- Regulation (EC) No 726/2004
- Commission implementing Regulation No 520/2012 of 19 June 2012 on the performance of pharmacovigilance activities
- Guideline on good pharmacovigilance practices – Module V – Risk Management Systems (Rev 1)
- RMP template
- European Commission Guidelines on the details of the various categories of variations, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products and on the documentation to be submitted pursuant to those procedures
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