The Risk Management Plan (RMP) is a key regulatory document that must be prepared on a mandatory basis for every medicinal product authorised in the EU. It describes a medicinal product’s safety profile, identifies known and potential risks, and defines risk minimisation measures. The legal basis is Implementing Regulation (EU) No 520/2012 and the EMA guideline on Good Pharmacovigilance Practices (GVP), Module V.
Structure and content of the RMP
The RMP is divided into several modules. The safety specification covers the epidemiology of the target indication, preclinical and clinical findings, and identified and potential risks. Identified risks are those for which a causal relationship with the medicinal product has been established. Potential risks are issues for which a causal relationship is suspected but not yet confirmed. Missing information describes gaps in knowledge about the safety profile, such as missing data for specific patient populations, for example children or pregnant women.
The pharmacovigilance plan defines which routine monitoring and which additional activities are carried out to continuously monitor the safety profile. Additional activities may include, for example, Post-Authorisation Safety Studies (PASS) or registry studies. The risk minimisation plan describes both routine measures (e.g., product information, prescription-only status) and additional risk minimisation measures such as educational materials for physicians or patient cards.
RMP in the marketing authorisation procedure
The RMP is an integral part of the marketing authorisation application (Marketing Authorisation Application, MAA) and is submitted together with the dossier to the EMA or the national authorities. In the centralised procedure, the EMA’s PRAC (Pharmacovigilance Risk Assessment Committee) reviews the RMP. After authorisation, the RMP must be updated regularly—particularly when new safety information becomes available, when the Periodic Benefit-Risk Evaluation Report (PBRER) is submitted, or when the marketing authorisation is varied. The marketing authorisation holder is responsible for keeping the RMP up to date.
Parallel submission of the RMP in multiple EU Member States in the decentralised or mutual recognition procedure (DCP/MRP) requires a consistent presentation across all countries. Coordinated review comments from the participating Member States can necessitate extensive revisions to the RMP, so sufficient planning time should be allowed for iterations. In particular for new active substances (New Chemical Entities), authorities regularly request detailed justifications for the classification of risks as well as extensive evidence from supporting studies before accepting the RMP as finalised. Accordingly, an experienced regulatory team is of high importance when drafting the document and negotiating it with the competent authorities.
Risk minimisation measures in practice
Additional risk minimisation measures (aRMM) are required by the EMA when routine measures are not sufficient to reduce known risks to an acceptable level. Typical aRMM include training programmes for physicians and pharmacists, controlled access programmes (pregnancy prevention programmes for teratogenic substances), patient alert cards or reminder cards, and specific information materials. The effectiveness of these measures is reviewed as part of effectiveness assessments. The results feed into updates of the RMP.
RMP and clinical trials
As early as clinical development, Phase II and Phase III studies provide essential data for the safety profile of the later RMP. The Development Safety Update Report (DSUR) compiles safety data from ongoing studies and forms an important basis for preparing the RMP. Contract research organisations (CROs) support sponsors with data collection and analysis as well as with the preparation of regulatory documents such as the RMP. Early scientific advice from the EMA can help align the scope of the required safety programme.
The close integration of clinical development and pharmacovigilance planning makes the RMP a living document that is updated throughout the entire development programme. Key milestones such as end-of-Phase II meetings with the EMA provide an opportunity to align the planned safety programme with the authority at an early stage. The scope and methodology of the required PASS studies, as well as the requirements for risk minimisation measures, can be discussed. Early and proactive communication with the EMA significantly reduces the risk of subsequent requests during the marketing authorisation procedure. For products with a known complex safety profile, the EMA recommends presenting the draft RMP already at the pre-submission meeting and incorporating feedback.
Frequently Asked Questions
When must an RMP be prepared?
An RMP is mandatory for all new marketing authorisation applications in the EU. The EMA may also request an updated RMP for major variations, new indications, or new patient populations. For generic medicinal products, a simplified RMP may be submitted under certain conditions, provided there are no additional risks compared with the reference medicinal product.
Who is responsible for preparing and updating the RMP?
Responsibility lies with the marketing authorisation holder (Marketing Authorisation Holder, MAH). The Qualified Person for Pharmacovigilance (QPPV) has professional responsibility for the quality of the pharmacovigilance system, of which the RMP is a part. In practice, specialised pharmacovigilance teams or contracted CROs often take on the operational drafting and maintenance of the document.
What are the most common deficiencies in RMP submissions?
Common deficiencies include an incomplete safety specification, missing or insufficiently justified potential risks, pharmacovigilance plans that are not sufficiently detailed, and missing effectiveness assessments for risk minimisation measures already implemented. As part of the assessment procedure, the EMA provides detailed feedback and requests improvements before a marketing authorisation is granted.
Regulatory References
- Implementing Regulation (EU) No 520/2012: Pharmacovigilance activities pursuant to Regulation (EC) No 726/2004
- EMA GVP Module V (Rev 2): Risk Management Systems
- EMA GVP Module XVI: Risk Minimisation Measures – Selection of Tools and Effectiveness Indicators
- ICH E2E: Pharmacovigilance Planning
- Directive 2001/83/EC (Human Medicines Directive), Article 8(3) and Annex I