3. The Risk Management Plan (RMP)

1. The Risk Management Plan (RMP)

(This section is organised in the form of a book, please follow the blue arrows to navigate through the book or by following the navigation panel on the right side of the page.)

Health authorities have increasingly adopted new regulations mandating companies to proactively manage the risk for all their medicines. Risk management planning and related activities may differ from one country/region to another in order to allow adaptation to each healthcare infrastructure, regulatory requirements and legal framework. In the EU marketing authorisation applicants are required to submit risk management plans (RMPs). These should include information on a medicine's safety profile and plans for pharmacovigilance activities designed to gain greater knowledge about the safety and efficacy of the medicine and also explain how risks will be minimised in patients and how those efforts will be measured.

The primary aim and focus of the RMP remains that of appropriate risk management planning throughout a medicinal product’s life cycle. It is designed to optimise the benefit-risk balance over time. For this purpose, it documents the risk management system considered necessary to identify, characterise and minimise a medicine’s important risks. The RMP contains:

1.  the ‘safety specification’: the characterisation of the safety profile of the medicine, concentrating on important identified and important potential risks and missing information, and also on which safety concerns need to be managed proactively or further studied;

2.  the ‘pharmacovigilance plan’: the planning of pharmacovigilance activities to characterise and quantify clinically relevant risks, and to identify new adverse reactions; it contains both routine and additional pharmacovigilance activities;

3.  the ‘risk minimisation plan’: the planning and implementation of risk minimisation measures, including the evaluation of the effectiveness of these activities.

The risk management plan evolves during the life-cycle of a medicine as knowledge regarding a medicine’s safety profile increases over time. The RMP is a dynamic document that should be updated throughout the life cycle of the product(s). This includes the addition of safety concerns where required, but also, as the safety profile is further characterised, the removal or reclassification of safety concerns.

An RMP or an update, as applicable, may need to be submitted to the Regulatory Authorities at any time during a product’s life-cycle,  As stated above, it is required for all new marketing authorisation (MA) applications. In addition, situations where an RMP or RMP update will normally be expected include:

• Application involving a significant change to an existing MA:
• New dosage form.
• New route of administration.
• New manufacturing process of a biotechnologically-derived product.
• Significant change in indication: this is a change of authorised indication(s) of a medicine where the new  target population differs materially from the one for which the medicine was previously authorised. This includes (but is not limited to): a new disease area, a new age group (e.g., paediatric indication).

• At the request of EMA or a national competent authority (NCA) when there is a concern about a risk affecting the benefit-risk balance.
• At the time of the renewal of the MA if the product has an existing RMP.
• An updated RMP should always be submitted if there is a significant change to the benefit-risk balance of one or more medicines included in the RMP.

1.1. Description of terms used in the RMP

The definitions from the Guideline on good pharmacovigilance practice (GVP, Annex I https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-annex-i-definitions-rev-4_en.pdf) apply also for the purpose of the RMP. However, the RMP should focus on those risks that are relevant (important) for the risk management activities for the authorised medicinal product.

• Identified risk (‘we know’): the risks that are undesirable clinical outcomes and for which there is adequate scientific evidence that they are caused by the medicine, e.g.,  demonstrated:

- by non-clinical findings and confirmed by clinical data
- in clinical trials or epidemiologic studies, by a significant difference with the comparator group, for which the size by which the difference is larger or smaller suggests a causal relationship (i.e. between the medicine intake and the occurrence of an adverse event)
- by spontaneous data sources, including published literature (e.g., a series of well-documented reports where causality is strongly supported by temporal relationship and biological plausibility)

Please note: not all reported adverse reactions are necessarily considered a relevant risk of the product in a given therapeutic context.

• Potential risk (‘there is a signal but we are not sure’): There is some basis for suspicion of an association between the medicine and the risk occurrence but it is not confirmed. Examples may be:

- Signals (non-clinical or clinical) that have not reached the level of evidence for an ‘identified risk’
- Findings observed in non-clinical studies (e.g., toxicology) but not in clinical studies
- Magnitude of difference observed in clinical studies raises suspicion but is not large enough to suggest a causal relationship
- Signal arising from spontaneous post-marketing reports

• Class-effects (chemistry, pharmacology, mechanism of action), based on prior knowledge and scientific or medical literature around other products belonging to the same class.

Please note: important potential risks included in the RMP would usually require further evaluation as part of the pharmacovigilance plan.

• Missing information (‘we don’t know’): There is no data or the data is insufficient about the safety of a medicine for certain anticipated utilisation (e.g. long-term use) or for use in particular patient populations. Usually additional data or evidence must be collected. Examples of such data could be:

- On a population level, after the medicine has been authorised, rare risks will become evident due to the exposure of a greater number of people to the medicine than were studied in clinical trials;
- On a sub-population level, e.g. in vulnerable groups such as children or pregnant women;
- At the individual level the efficacy and safety of medicines can vary, e.g., by genetic differences between individuals.

Please note: the absence of data itself (e.g., exclusion of a population from clinical studies) does not automatically constitute a safety concern. Instead, the risk management planning should focus on situations that might differ from the known safety profile.

Signal detection and management: A safety signal is defined as the information arising from one or multiple sources (including observations and experiments), that suggests a new, potentially causal relationship between an intervention and an event or a new aspect of a known association between an intervention and an event or set of related events. This may be either adverse or beneficial and it is considered to be likely enough to justify verification, i.e. it will be investigated or observed further. [Commission Implementing Regulation (EU) No 520/2012 Art. 19(1)]. A signal management process is a set of activities performed to determine whether there are new risks associated with an active substance or a medicine or whether known risks have changed, and includes any related recommendations, decisions, communications and tracking. The EU signal management process includes the following steps: signal detection, signal validation, signal confirmation, signal analysis and prioritisation, signal assessment and recommendation for action. These steps are defined in GVP Module IX (see also Lesson 1, Section 1.5 ‘the PhV Process in short’).

In practice, it is not always easy to differentiate between a ‘signal’ and a ‘potential risk’. Please refer to Lesson 2 in Course 3.

1.2. The ‘safety specification’ or the characterisation of the safety profile

The purpose of the safety specification is to provide an adequate description on the safety profile of the medicine (s), and specifically those aspects that need further risk management activities. It includes a summary of the important identified risks of a medicine, important potential risks, and missing information. It should also address the populations potentially at risk (where the product is likely to be used i.e., both as authorised and off-label use), and any outstanding safety questions (e.g., inherent to the medicine itself like toxicity, or related to the intended indication) that warrant further investigation to refine the understanding of the risk-benefit balance during the post-authorisation period. The safety specification forms the basis of the pharmacovigilance plan and the risk minimisation plan.

Finally, the perception of the risk is also an important aspect to take into consideration:

• The level of acceptance of the risk is usually low or there is no tolerance of any risk, when the medicine is intended to prevent a disease or to treat a non-life-threatening condition, e.g. vaccination or treatment of acne. This applies also if the target population is especially vulnerable (e.g. children) or except the intended indication young and healthy (e.g. young women and endometriosis);

• The level of acceptance of the risk is high when there are no or few therapeutic options for a life-threatening condition; e.g., second-line of chemotherapy for a metastatic cancer (a cancer that has spread).

1.3. The Pharmacovigilance plan

The pharmacovigilance plan proposes activities to better characterise and assess the risks during the lifecycle of a medicine. (e.g., to investigate frequency, severity, seriousness and outcome of a risk under normal conditions of use, and/or which populations are particularly at risk).

These pharmacovigilance activities can be categorised as:

Routine activities, also known as ‘passive surveillance’:

• Spontaneous adverse event reports are analysed by the MAH and regulatory authorities. The results are recorded in the European Pharmacovigilance database –part of EudraVigilance, and other in-house and international databases.
• Periodic Safety Update Reports (PSURs) are compiled by the MAH from event reports over a specific time period (usually since the compilation of the last PSUR, please refer to the following webpage for more information https://www.ema.europa.eu/en/human-regulatory/post-authorisation/pharmacovigilance/periodic-safety-update-reports-psurs) and include a reassessment of the benefit-risk balance. PSURs are submitted to the regulatory authorities.
• Data from different databases is routinely analysed to identify signals between adverse events over longer time periods. This activity is known as ‘data mining’.

 Additional activities are numerous and specific to each medicine’s safety profile. They may include:

• Non-clinical studies: including studies to better understand the mechanism of toxicity.
• Pharmacogenetic studies: i.e., investigating how genetic variations may impact how someone responds to a treatment.
• Stimulated report: using a specific process for adverse event reporting that stimulates healthcare professionals and patients to report adverse events (example: reporting can be stimulated by invitation from patients’ or consumers’ organisations to their members, or a class lawsuit).
• Active surveillance: a proactive and organised monitoring of the use of the medicine to better assess the number of adverse events in a given population, e.g. pregnancy follow-up. This could occur in doctor’s practices or hospitals involved in the risk monitoring, patient registries, electronic record research, etc.
• Non-interventional/observational studies: such as prospective (cohort), cross-sectional (survey) and retrospective (case-control) studies. For more information, please refer to Course 2 Lesson 3.
• Clinical trials: additional clinical trials may be required to investigate particular risks. For more information on a post-authorisation safety study (PASS), please refer to Course 3 Lesson 1.
• Medicine utilisation studies: studies that aim to monitor medicine usage.

1.4. The Risk minimisation plan

There are two types of activities:

• Prevention: Avoid occurrence of adverse  reactions (ADR) by identifying the risk factors and recommending against the use of the medicine by patients at-risk;
• Reaction: Stop a detected ADR from worsening:

a) Provide advice to the patient on what action to take (e.g., stop taking the medicine, report to doctor/pharmacist).

b) Provide treatment to reverse the ADR. This requires:

c) This may be supported by biological markers for early detection of effect.

Risk minimisation activities can be categorised as:

a) Routine activities:

• Level 1 - routine minimisation must ensure that suitable warnings are included with all product information including careful labelling, and packaging of the medicine. These routine minimisation activities include:
• Summary of product characteristics (SmPC).
• Package labelling.
• Package leaflet.
• Pack size(s).

 b) Additional activities: go beyond level 1 activities:

• Level 2 - additional risk minimisation activities that support communication and educational activities about a risk. This needs to be focused on certain risks and presented or communicated in a useful and meaningful way. Those activities must be integrated with other activities targeting the same audiences. They may include:
• Communication from the company to healthcare professionals such as: direct healthcare professional communications; doctors’ or pharmacists’ guides; education/training programmes, e.g., a pregnancy prevention programme; website; hotline.
• Communication from healthcare professionals to patients such as: alert card, patient monitoring card, patient acknowledgement form to confirm the understanding of the risk by the patient, website.
• Specialised product packaging to enhance safe use of the medicine.
• Legal status of the product (available by prescription only, over the counter).

• Level 3 - additional risk minimisation activities in relation to access to the medicine. They include different ways of increasing constraints at all levels and place new challenges to pharmacists and distributors, such as:
• Limit prescriptions to certain doctors (e.g., those that are specifically trained or certified), pharmacists or sites (e.g., hospitals).
• Manage prescriptions through conditions of reimbursement.
• Treatment conditional on inclusion in a mandatory registry.

These activities depend on each healthcare system and require a process to monitor the effectiveness of the activities. All these activities should be adapted to local requirements, i.e., in each country.

All minimisation activities require:

• Careful design before implementation. This should include testing or feasibility phases involving all stakeholders who will be involved in the activities. This might include doctors, nurses, pharmacists, patients, patient organisations.
• Implementation plan describing how, when, where and with whom they will be implemented.
• Regular measurement of their effectiveness during implementation is mandatory.