On 28th March 2017 EMA released the updated version of GVP Module V revision 2 which became effective from 31st March 2017. Along with this, Guidance on the format of the Risk Management Plan (RMP) in the EU – in integrated format (EMA/PRAC/613102/2015 Rev.2) was revised too. This is the most significant revision since the initial release.
The revised guidance has been updated in parallel to an amended RMP template for initial marketing authorisation applications. Key changes in the revision include:
- The focus should be on important identified or important potential risks and missing information
- Guidance on the expected changes in the RMP during the life cycle of the product
- Updated requirements for different types of initial marketing authorisation applications, with the aim to create risk-proportionate RMPs
- Removal of duplication within GVP Module V and other guidance documents
The revision requires MAHs and Applicants to characterize and quantify all clinically relevant risks and not just serious clinical relevant risks.
The three main components of the RMP, important identified risks, important potential risks and missing information, are further elaborated as follows:
- The identified risks of the medicinal product may be linked to situations such as off label use, medication errors or drug interactions. However an important identified risk to be included in the RMP would usually warrant further evaluation as part of the pharmacovigilance plan and risk minimization activities.
- The important potential risks to be included in the RMP are those important potential risks that, when further characterised and if confirmed, would have an impact on the risk-benefit balance of the medicinal product. Important potential risks included in the RMP would usually require further evaluation as part of the pharmacovigilance plan.
- Missing information: The absence of data itself (e.g. exclusion of a population from clinical studies) does not automatically constitute a safety concern. Instead, the risk management planning should focus on situations that might differ from the known safety profile. A scientific rationale is needed for the inclusion of that population as missing information in the RMP.
Principles of risk management: The need to continue additional risk minimisation activities may change, as the recommendations for specific clinical measures to address the risk become part of routine practice such as inclusion into standard treatment protocols in the EU, or in response to the findings of effectiveness of risk minimisation evaluations (i.e., they may need to be replaced with more effective activities). Some risk minimisation activities might be needed to be retained for the lifetime of the medicinal product (e.g. Pregnancy prevention programs).
Overview of the format and content of the risk management plan (RMP) – few important updates to the format include:
- The amount of drug safety information, particularly in RMP part II, should be proportionate to the identified risk and the potential risk, and will depend on the type of medicinal product, its risks, and where it is situated in its life cycle (by reference to DIR Art 8(3)).
- Article 14(2) of Regulation (EC) No 1394/2007 provides for a specific framework for RMP for Advanced Therapy Medicinal Products (ATMP).
- It is recommended, where appropriate, that the RMP document includes all relevant medicinal products from the same applicant/marketing authorisation holder containing the same active substance(s) (i.e., the RMP is an active substance-based document) [IR Art 30(2)].
In the context of a centralised procedure, the RMP should be submitted as part of an eCTD submission; however, for non-centralised procedures the RMP submission might still be part of a CTD submission.
Other important updates:
Part II, SII “Non-clinical part of the safety specification”: this section would only be expected to be updated in case of new non-clinical data that impacts the safety concerns. Safety concerns which are no longer relevant and/or have not been confirmed when sufficient relevant post-marketing experience and evidence are gathered can be removed.
Part II, SIII “Clinical trial exposure”: rather than focusing on exclusion during clinical trials, what is important is information on the low exposure of special populations or the lack thereof (e.g. pregnant women, breast-feeding women, patients with renal impairment, hepatic impairment or cardiac impairment, populations with relevant genetic polymorphisms, immuno-compromised patients and populations of different ethnic origins) should be provided where available and as appropriate.
Part II, SVII section “Identification of safety concerns in the initial RMP submission”: This section is expected to be “locked” and not change after the approval of the initial RMP.
Part II, SVII section “Identification of New safety concerns and reclassification with a submission of an updated RMP”: In the post-authorisation phase, it is expected that newly identified important and potential risks of the product are presented in the safety section of the dossier together with an evaluation on whether the risks should be considered important and added in the Safety Specification in the RMP. While the details of any new important identified or important potential risks should be provided in the RMP, the rationale should not be duplicated from that included in the dossier.
Part III: includes a table which summarizes minimum RMP requirements for initial marketing authorisation very clearly.
RMP Annexes: the annexes have been refined and Annex 8: “Summary of changes to the risk management plan over time” was added
Periodic safety update report and risk management plan: outlines the RMP modules (Part II module SIII, SV, SVII, SVIII and Part V) that contain similar information to the PSUR but provides clarity that they may not be in identical format and may not be interchangeable.
New sections added: New applications under Article 10(4), i.e., “biosimilar products” and new applications for homeopathic and herbal products not falling within the scope of the simplified registration.
Conclusion: The recent updates to Module V provide further guidance to MAHs and are aimed towards a more risk-proportionate approach based on evidence rather than merely pulling data into the document. The emphasis of the revision is on important identified risks, important potential risks and missing information and their simplified definitions. Removal of duplicate or redundant information across different modules will reduce some effort.
There are significant updates in new areas such as for advanced therapy medicinal products (ATMP) which discuss risks to living donors and to patients related to quality issues, storage and distribution, administrative procedures etc. which need to be considered carefully. MAHs must go through the updates thoughtfully as it will result in significant changes, albeit mostly with an opportunity to streamline the content and present the RMP as a more concise, scientific document.
The EMA provided guidance that Marketing authorisation holders and applicants may still use the first revision of the template:
- Until 30 September 2017 for RMPs submitted with the initial marketing authorisation application and responses to day 120 list of questions;
- Until 30 March 2018 for all other RMP submissions, including D91 responses for an initial application under accelerated assessment.
With the timelines fast approaching, Sciformix can help MAHs with implementing the new requirements, including revising RMP templates. Contact us to know more about how we can help.