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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.
On Friday, March 31, 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 emphas 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:
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:
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
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:
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:
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.
Janine Collins, MBBS, LLM, Sr. Director, European Risk Management, and Dafna Bonneh-Barkay, PhD, MSc, Sr. Project Manager
Posted with permission from UBC, view the original blog post here.