V.C.2. Submission of a risk management plan to competent authorities in the EU

For centrally authorised medicinal products, the RMP should be submitted as PDF files within the eCTD submission. Following a Commission decision where the procedure has involved the submission of an RMP, marketing authorisation holders should submit the RMP annex 1 in XML format within a specified timescale. RMP annex 1 provides the key information regarding the RMP in a structured electronic format which, following validation at the Agency, is uploaded into an Agency database that is accessible and searchable by the Agency and the competent authorities in the Member States. The system for nationally authorised medicinal products varies across Member States and the national requirements should be followed.

Details of new submission requirements and the electronic format will be provided on the Agency and Member State’s websites, as appropriate, and may in future replace the requirements in the paragraph above.

The initial RMP should be submitted as part of the initial marketing authorisation, or if required, for those products that do not have an RMP, through the appropriate post-authorisation procedure.

V.C.2.1. Risk management plans updates

An RMP update is expected to be submitted at any time when there is a change in the list of the safety concerns, or when there is a new or a significant change in the existing additional pharmacovigilance or additional risk minimisation activities. The significant changes of the existing additional pharmacovigilance and risk minimisation activities may include removing such activities from the RMP. For example, a change in study objectives, population or due date of final results, or addition of a new safety concern in the key messages of the educational materials would be expected to be reflected in an updated RMP with the procedure triggering those changes.

An update of the RMP might be considered when data submitted in the procedure results or is expected to result in changes of routine pharmacovigilance activities beyond adverse reaction reporting and signal detection activities, or of routine risk minimisation activities recommending specific clinical measures to address the risk. For example, an RMP update might also be warranted with a significant change of the plans for annual enhanced safety surveillance (routine pharmacovigilance activity), or when monitoring of renal function is added as a recommendation in the Special warnings and precautions for use section 4.4 of the SmPC (routine risk minimisation activity). The need to update the plans to evaluate the effectiveness of risk minimisation activities should also be considered with such updates.

When an emerging safety issue is still under assessment (as defined in GVP Module VI), in particular in the context of a signal or potential risk that could be an important identified risk, an RMP update may be required if the emerging safety issue is confirmed and the important identified or potential risk requires to be added to the list of safety concerns in the RMP.

Unless requested otherwise, a track-changes RMP document should be included with every RMP update, showing changes introduced in the latest update (as applicable), as well as compared with the “current” approved version of the RMP.

A medicinal product can only have one “current” approved version of an RMP. If several updates to the RMP are submitted during the course of a procedure, the version considered as the “current” approved RMP for future updates and track-changes purposes shall be the one submitted with the closing sequence of the procedure. When an RMP update is submitted with a procedure, the RMP is considered approved at the end of the procedure, when all changes are considered acceptable.

In the post-authorisation phase, submission of a new or updated RMP outside of another regulatory procedure constitutes a variation in accordance with the Guidelines on Variations (10). For detailed guidance on relevant variation categories and their classification, please also refer to the EMA Practical Questions and Answers to Support the Implementation of the Variations Guidelines in the Centralised Procedure (11).

RMP management with parallel procedures

If a medicinal product has more than one concurrently on-going procedure which requires submission of an RMP, ideally a combined RMP should be submitted with appropriate separation of data in RMP module SIII. The best regulatory path for the RMP update in case of multiple procedures potentially impacting on the RMP content should be discussed with the competent authority before submission.

RMP updates with the PSUR

If, when preparing a PSUR, there is a need for changes to the RMP as a result of new safety concerns, or other data presented in the PSUR, then an updated RMP should be submitted at the same time. In this case no stand-alone RMP variation is necessary. Should only the timing for submission of both documents coincide, but the changes are not related to each other, then the RMP submission should be handled as a stand-alone variation.

However, in the context of a PSUR EU single assessment (PSUSA), submission of RMP updates cannot be accepted together with the PSURs of medicinal products (centrally and/or nationally authorised). Marketing authorisation holders should take the opportunity of another upcoming procedure to update their RMP. Alternatively, marketing authorisation holders should submit a separate variation to update their RMP.

For nationally authorised medicinal products, RMP updates should be submitted to the competent authorities in the Member States for assessment.