3. The Risk Management Plan (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.