One global plan or several local ones
A first marketing authorisation application in several countries forces decisions on the risk management plan: whether to keep one global plan or to tailor local plans from the start, which format a global plan takes, and how the plan and its writer stay aligned with the rest of the submission dossier.
The plan's place in a first application
The first requirement to submit the risk management plan (RMP) comes with the first marketing authorisation application (MAA). Although the RMP follows specific requirements and guidance that relate mostly to the post-authorisation setting, it is a key deliverable in the global submission dossier for MAAs in the EU and in other countries with similar RMP requirements, such as China or Japan. So the RMP needs to be included in the overall submission plan and in the strategic discussion and decision-making meetings that select the appropriate data presentation and ensure that key safety messages are aligned across the submission documents. Decisions on its content, data presentation, risk subset and related activities are nevertheless specific to the RMP and may deviate from the overall strategy applied in the other submission documents. In this context, close collaboration with the other functions involved in preparing the submission dossier is crucial.
Like every submission document, an RMP submitted for a first MAA or a line extension requires thorough planning, communication and preparation well ahead of the submission date. Its content may vary significantly with the submission strategy, upfront alignment with health authorities and internal interfaces, and strategic considerations such as when to submit, in which country, for which indication and with which status of available data. On top of the decisions made for the entire submission dossier, such as the planned indications or the included populations, the RMP requires additional, central decisions: which safety concerns need to be included in the first RMP, and which pharmacovigilance activities and risk minimisation measures need to be planned and conducted.
Global and local plans
The RMP reflects the list of safety concerns (important identified risks, important potential risks and missing information) and the related pharmacovigilance activities and risk minimisation measures agreed with an individual health authority. For this reason it is considered a local document, linked to the summary of product characteristics (SmPC) of an individual country. A company that plans an MAA in more than one country at the same time should first clarify which RMP format, content and requirements most countries would accept.
One possible strategy for handling various local regulations and RMP requirements is a global RMP. A global RMP is not necessarily submitted to the health authorities, but it can serve as a central document that is amended and supplemented to fulfil country-specific requirements. A company submitting an MAA should therefore decide which strategy best serves its needs: one global RMP that is submitted or serves as a platform for local RMPs across countries, with specific modifications to meet local requirements, or individual local RMPs established from the beginning, for example tailored to individual countries or regions, and independent of each other. This strategic question has a considerable impact on the maintenance and oversight of the RMP and its potentially multiple versions. Both options have advantages and challenges.
| Type of RMP | Advantages | Challenges |
|---|---|---|
| Global RMP | Aligned content (data, data cut-off, safety concerns, pharmacovigilance activities, risk minimisation measures, indications, doses, intended populations, etc.)Facilitates maintenance and oversightCompany opinion reflected in line with the company core data sheetCan serve as a basis for local RMP deviationsCan be prepared ahead of time to support discussions and decisionsFacilitates and accelerates the preparation of subsequent local RMPs | Prepared to support local submission, so likely not, or not always, submitted as suchHow to align diverging health authority feedbackAn update of the global RMP after a local, country-specific change request from a health authority might make the RMP submitted in other countries obsolete and might lead to repeated roll-outs and resubmissions, with which local health authorities might disagreeDepending on the submission date, or with submission in several waves, new or further data may be available, raising the question of how to harmonise data lock points and content |
| Multiple local RMPs (including the EU RMP) | A tailored RMP complies with local regulatory requirements, health authority feedback and the local SmPCFacilitates tracking and oversight of local requirements and contentWithout further change requests, a local RMP requires no further updates | More maintenance work on various local RMPs and versionsResponsibility needs to be defined (global pharmacovigilance department or local affiliate) |
The first clear advantage of a global RMP is that it can be used as a basis for local adaptations, serving as an operating platform that facilitates all downstream activities.
The format of a global plan
The content, format and template of the first RMP need to be discussed in light of the planned submission waves and the country in which the RMP will be submitted first. This is critical if the first RMP will serve as the basis for subsequent local RMPs. Where the first submission wave is in Europe, the question of format does not arise, because the RMP would be based on the European RMP format. Where other countries come first, especially if submission in the EU will follow shortly or is at least planned, the EU format will likely be a plausible or even the best option, because of its wide acceptance across the world and its broad spectrum of topics and content. A global RMP based on the EU format can then be adjusted to local requirements, for example with region- or country-specific annexes.
How the versions diverge after submission
A first RMP finalised and submitted, potentially useful as a basis for further local RMPs or even submittable as such, is an important milestone, but only one of many in a multinational submission project. Once the RMP is submitted, defined processes are set in motion: authority feedback, change requests and questions affect its content and usually lead to updates and resubmissions, while other issues raised by the health authorities are addressed in parallel. Depending on how closely the submission waves are timed, several local versions of the RMP may need to be updated in parallel. Requests from different authorities might also diverge considerably, leading early on to content deviations between the local RMPs for different countries. This may even affect such central topics as the indication wording, the populations that may be treated, or which risks are associated with a certain population's use of the medication.
In the EU, the RMP is assessed as part of the dossier submitted for a first MAA, in a decentralised or centralised procedure, and it sits in Module 1.8.2 of the electronic Common Technical Document (eCTD). At defined time points of the agency review, the applicant receives questions on the submitted documents. The RMP may need to be revised either as a consequence of questions and requests received for other documents, such as the summary of clinical safety or the SmPC, or following RMP-specific questions and requests. The applicant submits the revised RMP and the related responses to the European Medicines Agency (EMA) according to a defined time schedule. The updated RMP and the responses need to be in line with the other resubmitted documents and responses, and very close internal interaction and alignment is needed across these documents.
Depending on the feedback received and the changes made, the updated RMP might no longer be suitable for submission or resubmission to health authorities in non-EU countries. The approved indication or target population, dose, trade name, safety concerns or required measures, such as the conduct of a post-authorisation safety study or obligations that are part of the approval, might not apply outside the EU, and other local RMP versions will then need to be prepared.
Drafting ahead of submission
A global RMP can leverage team resources and help accelerate some decisions upstream in the preparation of the document. Its drafts can be prepared early in the submission process, even far ahead of the start of submission activities. Early drafts facilitate content discussions and make questions and needed decisions more tangible for those who need to contribute to the document. They also facilitate and accelerate the preparation of subsequent local RMP versions tailored to country-specific needs. Adjusting an existing document saves time and resources, and it requires less effort than preparing a new document from scratch for each local submission. As time is one of the essential factors in submission projects, a document readily available that addresses the requirements of many authorities across the world is a considerable benefit.
Workload is a further crucial factor in submission projects, so whether to prepare a document that goes beyond what is absolutely necessary needs to be thought through upfront: how many resources can be spent on the document, which is one among many needed for the first MAA; how many further submission waves are planned, how soon and in which countries; and whether the EU format will be useful for the requirements to be fulfilled there. Depending on the submission strategy, preparing an additional, central document may add to complexity and workload, and may even outweigh the benefits of having a global RMP. For complex submission scenarios with multiple waves in various countries, however, a global RMP may streamline the process, support oversight and accelerate the submission preparation.
An alternative way to accelerate RMP preparation is a development RMP, put in place at an early stage of clinical development and kept up to date, so that at least some of its text and analyses can be used for the submission RMP. The same decisions on content, format, supporting data to be generated and resources still need to be made for the development RMP.
The plan's writer in the submission team
One challenge of RMP strategy and preparation is intrinsic to the stand-alone nature of the document and, where applicable, to the company structure. If the RMP is prepared by pharmacovigilance writers other than those responsible for the clinical documents of the submission dossier, it is key that the RMP's writer is always kept in the loop, participates in relevant meetings, is informed about the latest decisions on responses and strategies, and closely aligns with the clinical writers and the authors of the other documents.
The RMP may not be the first document that comes to mind for a submission dossier, and it is sometimes not in the focus of teams working on a first MAA. So the submission team needs to be made aware of the RMP requirement well in advance, and the RMP's writer needs to ensure that the timelines of the other submission documents allow the RMP to be finalised.
Further key aspects of preparing the RMP within the submission dossier are strategic thinking and planning well in advance, close collaboration with all relevant internal interfaces, and communication with the health authorities. Depending on health authority feedback, high flexibility is needed to update the RMP and to replan strategies. Related to the other clinical submission documents but unique in its content requirements and its local versions, the RMP is a dynamic document that requires timely strategic decisions and adaptations.