Taking the plan from kick-off to approval
An EU risk management plan is produced in five phases, from the kick-off of its preparation to the updates that follow approval. Its agency review differs between the centralised and the decentralised procedure, and it is updated on triggers rather than on a schedule.
The requirement across authorisation procedures
A risk management plan (RMP) is part of the submission dossier and is required for all new marketing applications planned for submission in the EU or European Economic Area (EEA), regardless of the authorisation procedure. In Europe four authorisation procedures exist: centralised, decentralised, mutual recognition and national. A new marketing application is submitted via one of the four depending on the type of medicinal product, the intended therapeutic indication and several other legal regulations. For initial marketing authorisation applications an RMP is required for all medicinal products.
The five phases
In general, an RMP undergoes a preparation phase, followed by a writing and review phase, a finalisation phase, an agency review phase, and finally the post-approval phase.
In the preparation phase the pharmacovigilance medical writer conducts kick-off meetings with the team, which raise the team's awareness of the upcoming task and clarify timelines, responsibilities and deliverables. The meetings also permit discussion of the content, the required analyses, the planned pharmacovigilance activities and the risk minimisation measures, among other topics. The writer then prepares a so-called shell RMP, which contains all the required information that can be provided independently of the statistical data outputs; epidemiological, non-clinical and pharmacokinetic information, for example, is usually available well in advance and can be finalised at an early stage. The aim of this front-loading is to agree in advance on the key outline of the RMP and on the required analyses, pharmacovigilance and risk minimisation measures, and to free up the team's capacity for interpreting the data during the subsequent writing and review. Preparing the shell RMP includes one or two review cycles in the team and meetings to discuss the comments, and to the extent possible the writer then finalises it before the statistical analyses arrive.
In the writing and review phase the writer creates first and final draft versions of the RMP, taking into consideration the statistical data analyses and their implications for the medicinal product, such as whether the safety concerns observed so far are in line with expectations and whether additional measures are required. The drafts are reviewed and thoroughly discussed in the team before they are sent to management for review and company approval. The RMP is also aligned with the other documents of the submission dossier in this phase, because it is important that the entire dossier is consistent and tells the same overall story. A thorough quality check against the source data is performed in this phase too.
In the finalisation phase the writer takes the last management decisions into consideration and then finalises the content of the RMP. The RMP then undergoes the last technical steps in the electronic document management system, which are required to deliver a high-quality document for electronic submission and include checking the format, setting hyperlinks and electronic approval in the system. After these steps the RMP is available for electronic submission to the agency.
Agency review and post-approval in the centralised procedure
In the centralised procedure the agency review follows a defined review schedule. The advantage of this procedure is that the timelines of the agency's questions are known well in advance, which facilitates internal capacity and timeline planning enormously. Depending on the type of questions received, the RMP will be updated several times during the agency review. Besides updating the RMP, the writer helps the team with the responses to the questions on it. These questions can concern, for example, the reclassification, addition or demotion of proposed safety concerns, additional data analyses, requests for post-approval measures, and changes to the proposed labelling, that is the Summary of Product Characteristics and the Package Leaflet. Towards the end of the approval procedure the frequency of agency interaction increases and RMP updates can be requested several times at extremely short notice, so good team interaction and internal processes that allow for these demands are crucial. In this last phase the agency also reviews RMP Part VI, the public summary of the RMP written in lay language. If positive opinions are obtained from the Pharmacovigilance Risk Assessment Committee and the Committee for Medicinal Products for Human Use, the European Commission approves the new medicinal product.
The first task in the post-approval phase of the centralised procedure is preparing and submitting RMP Annex 1 within the required timelines. Annex 1 provides the key information regarding the RMP in a structured electronic format, and a pharmacovigilance medical writer can prepare it in collaboration with selected team members. After that, the RMP is subject to various updates and needs to be maintained for as long as the product is on the market.
Agency review and post-approval in the decentralised procedure
In the decentralised procedure the RMP follows the same preparation, writing and review, and finalisation phases as in the centralised procedure, but its agency review differs. The applicant receives not consolidated comments from one agency but several comments from different national agencies, according to various local requirements and with different review timeframes. A major challenge for the applicant is to consolidate all these comments, both in content and in timing. For example, changes requested by one national agency may be implemented globally in the RMP and so apply to other countries as well, or they may apply to that one country only, in which case the question arises whether it is advisable to create local versions of the RMP. The requirements for RMP Annex 1 and the handling of RMP Part VI differ as well, because these also follow local requirements. In the post-approval phase any of the national agencies involved can request RMP updates at any time, not only a single central body such as the European Medicines Agency (EMA). This can raise the same questions as in the agency review phase, such as whether requested updates apply to all countries or are country-specific.
Updates and their triggers
Unlike periodic benefit-risk evaluation reports and development safety update reports, RMPs do not follow a periodic schedule: an RMP must be submitted with an initial marketing authorisation application and is then updated following certain triggers. The RMP is not prepared just once for the marketing authorisation application but is a living document that will be updated multiple times during the evaluation of the application and thereafter. RMPs are continually updated throughout the product life cycle as new information becomes available.
RMP updates have many triggers, for example an ad hoc agency request, changes in the safety concerns or the benefit-risk evaluation, and completion of milestones in the pharmacovigilance plan. The EMA or a national competent authority within the EU or EEA can request an update if it considers one necessary, and an update is then required. For the other triggers the accounts differ: one requires an update whenever the risk management system changes, that is when new information leads to a significant change in the benefit-risk profile, when the result of an important pharmacovigilance activity is obtained or when a risk minimisation milestone is reached. Another requires an updated RMP whenever new information may significantly affect the benefit-risk profile or when an important pharmacovigilance or risk minimisation milestone is reached. A third says an RMP is updated when new information becomes available that may have an impact on the benefit-risk profile, and that it may also be updated when an important pharmacovigilance milestone is reached, for example when the results of a post-authorisation safety study become available. The timing of RMP updates is therefore unpredictable, and there may be situations when an update needs to be submitted at short notice.
The frequency of RMP updates should be proportionate to the risks of the product. When an existing RMP prepared according to Revision 1 of GVP Module V is updated, it may be necessary to adapt its safety concerns to the current definitions.