NEW! EMA Guidance on RMPs in the EU
NEW! EMA Guidance on RMPs in the EU
On Friday, 31 March 2017 the EMA released the revised Module V- Risk Management Systems (Rev 2) of Good Pharmacovigilance Practice (GVP) (EMA/838713/2011 Rev 2) accompanied by a revised Guidance on the format of the risk management plan (RMP) in the EU – in integrated format (EMA/PRAC/613102/2015 Rev.2).
Rev 2 of Module V and the template provide welcome changes to the RMP by focussing on the RMP as being a dynamic, scientifically based, risk- proportionate document where much of the previous cumbersome duplication across modules has been removed. It provides valuable clarification in several previously grey areas and should result in an RMP that is a valuable document for all stakeholders.
The emphasis is now is on a concise, scientifically focussed document where the amount of information provided is proportionate to the risk. This applies to all modules of the RMP and specifically the epidemiology section which previously had often become overly lengthy and detailed Information should be provided in sufficient detail but avoiding unnecessary text which would distract from the key issues to be considered. The safety specifications should not be a duplication of data submitted elsewhere in the dossier, unless sections are intended as common modules with other documents (such as the PSUR).
However, converting an RMP from the Rev 1 format to Rev 2 will not be a simple matter of condensing and copy/pasting. The content requires scientific rationale and justification throughout with a critical need for in-depth understanding of the safety profile of the product. An overview of the major changes in Rev 2 is discussed below.
Timelines for implementation
Both came into effect on the day of issue, 31 March 2017. The EMA has stated that RMPs submitted for initial market authorisation applications and Day 121 responses applying GVP Module V Rev 1 will be accepted for a further 6 months, and all other RMP submissions (including Day 91 responses for an accelerated application under accelerated assessment) will be accepted for one further year until March 2018. Thus, all RMPs submitted after 31 March 2018 will be required to be submitted in accordance with Rev 2 of Module V and comply with the Rev 2 format.
Clarification of risks and missing information to be included in the RMP
Although the definitions remain unchanged as per GVP Annex 1, Module V Rev 2 provides clearer guidance on what should be considered for inclusion in an RMP.
For important identified risks, the RMP should focus on those which have an impact on the risk- benefit balance of the product and would usually warrant:
Further evaluation as part of the pharmacovigilance plan
- Risk minimisation activities (routine or additional)
There is clearer guidance as to when and when not to include missing information. Previously there had been a tendency to include all populations not studied in the clinical development programme as missing information. The guidance emphasises the need to think about the anticipated utilisation of the product and whether the lack of data is relevant. The absence of data itself does not automatically constitute a safety concern. A scientific rationale needs to be provided for the inclusion of a population as missing information.
RMP as a dynamic document
There has been concern in the past from many stakeholders that, over time, the number of important risks in an RMP would increase, with no opportunity for any to be removed or modified. Rev 2 emphases that the RMP is a dynamic document where, over time, whilst safety concerns may be added, there is also the possibility to remove or reclassify risks as the safety profile is further characterised. For example:
Important potential risks may be removed if
accumulating data do not support the initial supposition
the impact on the individual has been demonstrated to be less than anticipated and hence the risk in not important
there is no reasonable expectation that any PV activity can further characterise the risk
- accumulating data do not support the initial supposition
An important potential risk may be reclassified as an important identified risk based upon emerging evidence
Important identified risks may be removed in certain circumstances where the risk is fully characterised and appropriately managed. Such examples include those products that have been marketed for a long time for which there are no outstanding pharmacovigilance activities and/or risk minimisation activities have been fully integrated into normal clinical practice.
Missing Information could be removed over time if
New data has become available
- There is no reasonable expectation that existing or future feasible pharmacovigilance activities could provide relevant data
- New data has become available
Part II Module SVII
By far the biggest change in Rev 2 is the presentation of Module SVII which differs significantly from the previous guidance, in keeping with the ongoing theme of focussing on the RMP as dynamic document and a risk-proportionate RMP.
Major changes are
A sub module which sets out the safety concerns which were in existence at the time the product was approved for the given indication. The sub-module will be “locked” after approval and act as a reference point for the living document over time.
A specific sub module for new risks and for reclassification of risks.
Both important and unimportant risks are to be discussed with a justification as to why risks have been classified as not important
For each important identified risk and potential risk, an evaluation of the impact on the risk-benefit of the product
- Missing information data are now also to be presented in this module
Many of the elements previously in Module SVI Additional EU Requirements (overdose, medication errors, transmission of infectious agents, off label use) have been moved to Module SVII leaving only the potential for misuse in Module SVI.
However, these are not lost but should be considered in Module SVII along with:
risks in pregnant and lactating women
effects on fertility risks associated with disposal of used product
risks related to administration
paediatric safety issues
- justification if a class effect is not to be included as an important identified or potential risk
Part III Pharmacovigilance Plan
Rev 2 clarifies that routine PV activities which go beyond adverse reaction reporting and signal detection should be described (i.e., enhanced passive surveillance system, observed v expected analyses, cumulative reviews of adverse events of interest)
It also provides guidance on when to include or remove PASS protocols from the annexes and clarifies that studies imposed solely by other agencies outside of the EU should not be included in the EU RMP.
Part IV Post authorisation efficacy studies
The scope of this module is more restricted than in Rev 1. It makes it clear that this should only include a list of post-authorisation efficacy studies (PAES) imposed as conditions to the marketing authorisation or when included as specific obligations in the context of a conditional marketing authorisation or a marketing authorisation under exceptional circumstances. If no such studies are required, RMP Part IV may be left empty.
Part V Risk minimisation measures
There are no major significant changes to this module. However, Rev 2 does very helpfully distinguish SmPC and PL language between:
routine risk communication messages, and
- routine risk minimisation activities recommending specific clinical measures to address the risk
Rev 2 also addresses the fact that over time consideration should be given as to whether additional risk minimisation measures could be removed, for example, when these measures have become part of normal clinical practice.
Instead of the twelve previous annexes, there are now only eight. These reflect more closely relevant RMP information and eliminate information which would be found in other documents within the market authorisation dossier.
Rev 2 of Module V and the RMP template provide substantive changes for RMPs and provide a welcome risk proportionate approach. The documents have provided clarification on previous grey areas and allow clearly for a change to the risk profile over time with the opportunity to remove or modify risks as appropriate. As a result it is likely that a more scientifically valuable RMP will be created which is better adapted to considering the use of the product in the real world setting over time.
A well-prepared Risk Management Plan is critical to every product approval in the EU. Contact us to learn more about this latest guidance and how it might affect your product.
Click here to read and download the EMA’s full guidance on Risk Management Plans.