This document, “Guidance on the format of the risk management plan (RMP) in the EU – in integrated format” (EMA/164014/2018 Rev.2.0.1), is an official guideline from the European Medicines Agency (EMA). It provides a standardized template and detailed instructions for pharmaceutical companies (Marketing Authorisation Applicants/Holders) on how to create, structure, and update a Risk Management Plan for a medicinal product in the European Union.
The RMP is a critical document required for marketing authorization. Its primary goal is to proactively ensure that a medicine’s benefits outweigh its risks throughout its entire lifecycle by:
- Identifying and characterizing the product’s safety profile.
- Planning pharmacovigilance activities to learn more about the risks.
- Planning risk minimization measures to reduce the known risks.
Detailed Section-by-Section Explanation
Pages 1-3: Introduction and Checklist
- General Consideration and Guidance: This section sets the core principles for writing an RMP. It emphasizes being concise, scientifically based, and non-promotional. It instructs applicants to focus on information that adds value to understanding the product’s safety and how to manage it. It also introduces the requirement to link the RMP to other parts of the submission dossier (like the eCTD).
- Checklist for Writing or Assessing an RMP: This is a crucial tool for both applicants preparing an RMP and regulators assessing it. It is not part of the final submitted RMP but serves as a quality control guide. The checklist is divided according to the main parts of the RMP:
- Part II: Safety Specification: Ensures all relevant safety data has been reviewed, limitations are considered, and for generic products, that the safety concerns of the reference product have been addressed.
- Part III: Pharmacovigilance Plan: Checks that all safety concerns are covered, proposed studies are well-defined, feasible, and have realistic timelines.
- Part IV: Plans for Post-Authorisation Efficacy Studies: Confirms that all required post-authorization efficacy studies are included.
- Part V: Risk Minimisation Measures: Verifies if routine measures are sufficient or if additional activities are needed, justified, and feasible across the EU.
- Part VI: Summary of the RMP: Ensures the summary accurately reflects the full RMP without promotional content.
Pages 4-5: RMP Administrative Header
This section is the cover page for the RMP and contains vital administrative information:
- Product Name and RMP Version Number: A clear version control system (e.g., 0.1 for initial submission, 1.0 for final approval) is mandated.
- Data Lock Point (DLP): The date up to which safety data is included. It should be no more than 6 months old.
- Final Sign-off Date: The date the RMP was finalized for submission.
- Rationale for Update: Explains why a new version is being submitted (not for initial applications).
- QPPV (Qualified Person for Pharmacovigilance) Oversight: Requires a declaration or signature from the QPPV, confirming they have reviewed and approved the RMP. This is a key legal requirement.
Pages 6-7: Table of Contents
Provides a clear and structured overview of the entire RMP document, listing all its parts and modules.
Pages 8-9: Part I – Product Overview
This is a summary table with key product information, including:
- Active substance, pharmacotherapeutic group, and marketing authorisation holder/applicant.
- Invented name, type of marketing authorisation procedure (e.g., centralized, national).
- Brief description of the product (mode of action, composition).
- Indication(s), dosage, pharmaceutical form(s), and strength(s).
- Whether the product will be subject to “additional monitoring” in the EU.
Pages 9-28: Part II – Safety Specification (The “What do we know?” Section)
This is the core of the RMP, describing the product’s safety profile based on all available data. It is broken down into several modules:
- Module SI: Epidemiology of the Indication: Describes the disease, its incidence, prevalence, demographics of the target population, and standard treatments. This sets the context for risk evaluation.
- Module SII: Non-Clinical Part: Summarizes significant safety findings from animal and other non-human studies (e.g., toxicity, carcinogenicity) and discusses their relevance to humans.
- Module SIII: Clinical Trial Exposure: Provides detailed tables on the number of patients and duration of exposure from clinical trials, broken down by dose, age, gender, and ethnic origin. This helps identify limitations in the pre-approval safety database.
- Module SIV: Populations Not Studied in Clinical Trials: Explicitly lists populations excluded from trials (e.g., pregnant women, patients with severe renal impairment) and discusses the implications for predicting real-world safety.
- Module SV: Post-Authorisation Experience: For products already on the market, this provides an overview of the number of patients exposed and how the product is being used in practice (including any off-label use).
- Module SVI: Potential for Misuse: Discusses the potential for abuse or illegal use of the product and proposes measures to limit it.
- Module SVII: Identified and Potential Risks: This is the most critical module. It defines and justifies the list of Safety Concerns, which are categorized as:
- Important Identified Risks: Undesirable clinical outcomes with sufficient evidence of a causal link to the product (e.g., a known side effect).
- Important Potential Risks: Undesirable outcomes where a causal link is suspected but not yet confirmed.
- Missing Information: Gaps in knowledge about the safety in certain populations (e.g., children) or from long-term use.
- Module SVIII: Summary of Safety Concerns: A concise, tabulated list of all safety concerns identified in Module SVII. This table is a central reference point for the entire RMP.
Pages 29-33: Part III – Pharmacovigilance Plan (The “How will we learn more?” Section)
This part details the activities planned to address the safety concerns identified in Part II.
- Routine Pharmacovigilance: Describes activities beyond standard adverse event reporting, such as using specific follow-up questionnaires for certain risks.
- Additional Pharmacovigilance Activities: Describes specific studies (e.g., registries, cohort studies) imposed as conditions or obligations by regulators. For each study, the RMP must include its objectives, design, population, and clear milestones and due dates.
- Summary Table (Part III.1): A crucial table that gives an overview of all planned and ongoing studies, linking them to the safety concerns they address and their regulatory deadlines.
Pages 33-34: Part IV – Plans for Post-Authorisation Efficacy Studies
A separate section for listing any post-authorisation efficacy studies that are required as a condition of the marketing authorisation. This is distinct from safety studies.
Pages 34-39: Part V – Risk Minimisation Measures (The “How will we reduce the risks?” Section)
This part outlines the measures to prevent or reduce the risks associated with the product.
- Routine Risk Minimisation: This primarily refers to the safety information contained within the Summary of Product Characteristics (SmPC) and Package Leaflet (PL), as well as pack size and legal status (e.g., prescription-only).
- Additional Risk Minimisation Measures (aRMM): These are required when routine measures are insufficient. The guidance provides examples:
- Healthcare Professional and Patient Guides: Educational materials.
- Checklists: For prescribers to ensure correct patient selection and monitoring.
- Patient Alert Cards: To be carried by the patient to inform other healthcare providers of specific risks.
- Pregnancy Prevention Programmes: A comprehensive set of measures for products with teratogenic risks.
- Summary Table (Part V.3): A table that cross-references each safety concern with its corresponding pharmacovigilance and risk minimization activities, providing a complete overview of the risk management strategy.
Pages 40-44: Part VI – Summary of the Risk Management Plan
This is a stand-alone, public-facing summary written in plain language. It is intended for healthcare professionals and patients. It must be a true representation of the full RMP and includes:
- A description of the medicine and its use.
- The list of important risks and missing information.
- A summary of the risk minimization measures and planned studies.
Pages 45-51: Part VII – Annexes
These are the supporting documents for the RMP.
- Annex 1: Reserved for EudraVigilance electronic reporting requirements.
- Annex 2 & 3: Tabulated summaries and full protocols for pharmacovigilance studies.
- Annex 4: Specific follow-up forms for adverse reaction reporting.
- Annex 5: Protocols for post-authorisation efficacy studies.
- Annex 6: Extremely important. Contains the draft or approved key messages and materials for any additional risk minimization measures (e.g., the actual text for a patient guide or alert card).
- Annex 7: Other supporting data and referenced literature.
- Annex 8: A log of all significant changes made to the RMP over time, providing a history of its evolution.
Summary
This guidance document provides a comprehensive and highly structured framework for creating an RMP. It ensures that a medicine’s risks are proactively identified, thoroughly investigated, and effectively minimized, with all plans clearly documented and justified. The use of templates, tables, and checklists promotes consistency and clarity, facilitating the assessment by regulatory authorities and ultimately protecting public health in the EU.
