What the EU risk management plan is for and what it contains
The European Union's risk management plan sets out what is known and not known about a medicine's safety, how the remaining questions will be studied and how the risks will be prevented or minimised. Once accepted, it binds the marketing authorisation holder to the activities it describes. It is built of seven parts, the second of which, the safety specification, is divided into eight modules.
The plan's legal standing
In the European Union the risk management plan (RMP) is a legally binding regulatory document submitted to health authorities. It is more than a regulatory document or a regular safety report: it is also a legally binding administrative document with monetary implications. Once the health authorities accept it, the marketing authorisation holder is legally obliged to perform the activities it describes. An RMP is required for every new marketing authorisation application in the EU, apart from homoeopathic medicinal products registered through the simplified registration procedure and traditional herbal medicinal products. A single product requires a single plan, whatever its indications, formulations or dosage forms, unless a scientific rationale justifies otherwise and the health authority agrees.
What the plan is for
The RMP gives a detailed description of the pharmacovigilance activities and interventions designed to identify, characterise and manage the risks relating to a medicinal product. Its ultimate goal is to improve the benefit-risk balance by combining risk assessment with risk minimisation. It assesses the product in the context of a benefit-risk analysis in order to prevent or minimise the medicine's risk in patients.
The RMP aims to characterise the safety concerns and, as its name says, to plan how the risks will be further characterised and minimised in the pre- and post-authorisation phases. The risks have to be characterised thoroughly, by analysing and evaluating their circumstances, risk factors and pattern of occurrence, so that risk minimisation measures can be planned adequately. The RMP does more than describe and evaluate the safety concerns: it also gives information on how they will be managed once the drug is on the market. Its main purpose is to present the authorities with a plan for managing the safety concerns. It presents detailed pharmacovigilance activities to evaluate the safety concerns further and to minimise the risks, and measures to evaluate the effectiveness of additional risk minimisation.
The RMP is a comprehensive document that details the product's safety profile, a pharmacovigilance plan for collecting additional safety and efficacy data, and measures to mitigate the safety concerns associated with the product's use. It first describes what is known and not known about the safety profile. It describes the safety information still to be determined for the medicine and specifies the measures the company will take to address those gaps in its safety profile. Once what is known has been established, it outlines measures to prevent or minimise the risks and how the effectiveness of those measures will be assessed and monitored. It proposes pharmacovigilance activities to study further safety concerns during use of the drug in the real-life setting, and documents the need for efficacy studies in the post-authorisation phase. It also records all the commitments of the marketing authorisation holder on further plans to evaluate the effectiveness of the risk minimisation measures for managing patients' safety.
When the plan is prepared and updated
The first version of the RMP is prepared at the time of the first marketing authorisation application. Its submission also follows a risk-based approach: as soon as important safety knowledge or an important risk arises, an RMP has to be prepared or updated.
The first RMP, written for the marketing authorisation application in the EU, is built mainly on the safety concerns carried over from clinical development, together with any defined during the analysis done for the submission package. Unless the analysis of pooled clinical trial data for the first RMP defines new important identified or potential risks, its safety concerns are likely to be copied from the development safety update report (DSUR), probably with missing information added to the list under its current definition.
Unlike a clinical study report, a clinical summary or a periodic safety report, the RMP is a living document, not a periodic report: it is updated continuously throughout the lifecycle of the medicine, in the pre- and post-authorisation phases, though not necessarily at regular intervals, and an update may be needed at any point. As a medicine moves through its lifecycle, emerging evidence on safety and on efficacy or effectiveness needs to be evaluated in the context of baseline knowledge, and pharmacovigilance activities and risk minimisation measures are planned dynamically and in proportion to the risks. In this sense the RMP is also dynamic and proportionate to risks.
The plan's origins and adoption
The European Medicines Agency (EMA) introduced the plan in 2007, and since then one has been required for every marketed product from its first marketing authorisation application for as long as the product is on the market. Module V of the good pharmacovigilance practices (GVP) guidance switched the whole approach to risk management from spontaneous and reactive to continuous and proactive in dealing with patients' safety. The EMA published a revised GVP Module V on risk management systems (Rev 1) in April 2014. The RMP guidance has been transformed continuously since 2007 and has taken a logical shape in data flow, consistency and transparency, in a modular format suited to submission. Over that time the plan's focus moved significantly from drug safety to patient safety and from safety to the benefit-risk balance, and the requirement to evaluate the effectiveness of risk minimisation measures was introduced.
The RMP is considered one of the best examples of good pharmacovigilance practices for ensuring patients' safety, and it has been demonstrated to be one of the most effective pharmacovigilance tools and a key turning point for pharmacovigilance regulatory practice worldwide. The EMA's plan has been adapted worldwide, and health authorities other than the EMA and the US Food and Drug Administration deem it a reference, either for developing their own RMP guidance or for accepting the EMA's GVP guidelines. The plan has gained importance for newer products, especially those approved through procedures that give patients earlier access, such as conditional approval for orphan drugs, without compromising an efficient preliminary assessment of the product's safety. Such procedures often need more robust review by the health authorities and a stringent risk management strategy with additional pharmacovigilance activities or risk minimisation measures beyond the routine ones, which increases the holder's global cost of implementing the plan.
The seven parts and eight modules
The RMP is modular. It consists of seven parts, of which Part II, the safety specification, is further divided into eight modules. The EMA's plan has had this modular format since July 2012. Unlike other regulatory documents, it is not a single file: some of its parts are further subdivided into modules or appendices, and each part or module can be updated and resubmitted independently of the others. An initial application might not require every part or module. Normally all parts of an RMP should be submitted, but in certain circumstances some parts or modules may be omitted unless the competent authority asks for them.
Part I, the product overview, provides administrative and active-substance information. Part II, the safety specification, identifies what is known and not known about the medicine. Part III, the pharmacovigilance plan, plans a programme to identify new safety concerns and characterise known ones. Part IV, the plans for post-authorisation efficacy studies, investigates effectiveness in everyday medical practice. Part V, risk minimisation measures, takes steps to prevent or minimise known or suspected risks and evaluates the effectiveness of the risk minimisation measures. Part VI, the summary of the risk minimisation plan, provides a public summary of the RMP written in lay language. Part VII holds the annexes.
Part I and the safety specification
Part I provides administrative information about the RMP and an overview of the product, including active-substance information, pharmacotherapeutic group under the Anatomical Therapeutic Chemical classification, mode of action, indication, posology, and pharmaceutical forms and strengths.
Part II, the safety specification, gives a synopsis of the medicine's safety profile, which should include what is known and not known about it. Its eight modules all correspond to safety specification headings in ICH E2E except module SVI, which carries the additional elements the EU requires.
Module SI, the epidemiology of the indications and target populations, gives background information on the proposed indications, explaining what events occur as part of the disease and what events can be expected in the target population. It has to discuss the epidemiology of the indications, including incidence and prevalence and the demographics of the target populations; risk factors for the disease; main treatment options; mortality and morbidity; concomitant medications in the target populations; and important co-morbidities found in them.
Module SII is basically a summary of the non-clinical parts of the CTD. It presents a summary of the important non-clinical safety findings, such as toxicity, general pharmacology, drug interactions and other toxicity-related data. It should justify including or excluding non-clinical findings as important risks by their relevance for humans, and it should also note missing information. Safety concerns arising from non-clinical data should be carried forward to module SVIII.
Module SIII presents clinical trial exposure. It summarises, in tables, graphics or both, a variety of exposure measures from clinical trials, such as duration of exposure, dose levels or age groups.
Module SIV should discuss the subpopulations within the expected target population that clinical trials did not study, such as pregnant women or patients with severe renal impairment. It should also explain the relevance of the inclusion and exclusion criteria, particularly where an exclusion criterion from a study protocol is not proposed as a contraindication in the summary of product characteristics (SmPC). The populations typically discussed are children, the elderly, pregnant or lactating women, and patients with hepatic or renal impairment. Only the safety concerns still outstanding should be carried through to module SVIII.
Module SV, post-authorisation experience, is required only for updates of the RMP.
Module SVI carries the safety topics ICH E2E does not include: harm from overdose whether intentional or accidental, transmission of infectious agents, misuse for illegal purposes such as recreational use, medication errors, off-label use, and specific paediatric issues including the potential for paediatric off-label use and the safety and efficacy issues identified in the paediatric investigation plan. Safety concerns from this module have to be carried through to module SVIII.
Module SVII should give more information on the important identified and important potential risks. It should be concise rather than a collection of adverse events from clinical studies or a list of the adverse reactions in the undesirable-effects section of the summary of product characteristics, and it should contain only important adverse reactions, important interactions and important pharmacological class effects. For each important identified and important potential risk it has to give a variety of information, such as frequency, severity and nature of the risk, risk factors, and preventability.
Module SVIII summarises the safety concerns, including those identified in modules SII, SIV, SVI and SVII.
Parts III to VII
Part III, the pharmacovigilance plan, describes how the marketing authorisation holder identifies and characterises safety concerns by proactive monitoring. It does not include actions intended to reduce, prevent or mitigate risks. For each safety concern summarised in module SVIII the planned pharmacovigilance activities have to be listed, and they can be divided into routine and additional activities. Where safety concerns are well characterised, routine post-authorisation pharmacovigilance will suffice. Additional activities may be non-clinical studies, clinical trials or non-interventional studies. A safety concern with additional activities needs an action plan and a summary table that includes the expected dates of milestones.
Whereas Parts II, III and V are concerned with drug safety, Part IV deals with efficacy. The pharmacovigilance legislation provides the legal basis for requiring post-authorisation efficacy studies where there are concerns about efficacy in everyday medical practice, or where knowledge about the disease or about the clinical methodology used to investigate efficacy indicates that previous efficacy evaluations may need significant revision. For paediatric medicines and advanced therapy medicinal products, long-term follow-up of efficacy is required.
Part V divides risk minimisation into routine and additional activities. Routine activities may be the only ones proposed. An action plan has to be provided for how the effectiveness of additional activities will be evaluated.
Part VII consists of twelve annexes, among them the current or proposed product information, the worldwide marketing authorisation, and other supporting data such as referenced material.
Where the plan's information comes from in the dossier
The plan sits in Module 1.8.2 of the Common Technical Document (CTD). The RMP is a stand-alone document, so cross-references to other parts of the dossier should be avoided. Following GVP Module V, the information for each part and module of the plan is located in these CTD sections.
| RMP | CTD |
|---|---|
| Part I: Product overview | Module 2.3: Quality overall summary; Module 3: Quality |
| Module SI: Epidemiology of the indication(s) and target population(s) | Module 2.5: Clinical overview |
| Module SII: Non-clinical part of the safety specification | Module 2.4: Non-clinical overview; Module 2.6: Non-clinical written and tabulated summaries; Module 4: Non-clinical study reports |
| Module SIII: Clinical trial exposure | Module 2.7: Clinical summary, briefly; Module 5: Clinical study reports |
| Module SIV: Populations not studied in clinical trials | Module 2.5: Clinical overview |
| Module SV: Post-authorisation experience; Module SVII: Identified and potential risks | Module 2.5: Clinical overview, briefly; Module 2.5: Clinical overview (including the benefit-risk conclusion); Module 2.7: Clinical summary; SmPC |
| Module SVIII: Summary of the safety concerns | Module 2.5: Clinical overview; Module 2.7: Clinical summary |
| Part III: Pharmacovigilance activities | Module 2.5: Clinical overview; Module 2.7: Clinical summary |
| Part IV: Plans for post-authorisation efficacy studies | Module 2.5: Clinical overview; Module 2.7: Clinical summary |
| Part V: Risk minimisation measures | Module 2.5: Clinical overview; Module 2.7: Clinical summary |