Guidance on the format of the risk management plan (RMP) in the EU – in integrated
format
EMA/164014/2018 Rev.2.0.1 accompanying GVP Module V Rev.2
was too small and, therefore, a PASS investigating frequency of the risk was imposed. Cardiac
disorders should be classified as an important identified risk.
• If a serious adverse reaction was identified in clinical trials (e.g. Stevens Johnson Syndrome)
and, at the time of the initial marketing authorisation application, the incidence is considered
acceptable for a positive risk-benefit balance, routine pharmacovigilance activities could be
considered sufficient to monitor this risk assuming that the event is appropriately managed by
health professionals in clinical practice. The periodic risk-benefit evaluation (e.g. PSUR) will
therefore discuss the findings from spontaneous reporting and provide an evaluation on
whether the frequency of the event is higher than expected. However, if a signal is raised
following the use in clinical practice, the identified risk would be considered as an important
identified risk and additional pharmacovigilance activities should be considered to provide an
accurate estimate of the frequency and inform the risk-benefit evaluation.
Risk-benefit impact:
present the reasons for this classification, consider seriousness, frequency and
severity as determinants, e.g.:
• Serious adverse reactions (as described in GVP Annex I – Definitions) that result in death, are
life-threatening, result in persistent or significant disability or incapacity, or are a congenital
anomaly/birth defect, if not prevented or managed appropriately;
• Common adverse reactions that are so severe (Grade 3-4) that it may lead to a serious
outcome, discontinuing the treatment and/or reducing the efficacy of the medicinal product, if
not managed appropriately, even if the adverse reaction is not serious;
• Severe adverse reactions occurring with high frequency in the targeted population that could
have a severe impact on the patient (e.g. depression could significantly impact the quality of
life and it could also lead to the potential risk of suicide, therefore, it could be classified as in
important identified risk).
<Important Potential Risk 1>:
Examples of important potential risks are:
• QTc prolongation is a known adverse reaction of another medicinal product of the same class,
observed in clinical trials and included in section 4.8 of the SmPC; however, no events of
Torsade de Pointes have been observed in the clinical development programme or the
magnitude of QTc prolongation is lower than normally associated with Torsade de pointes.
Consequently, “Torsade de pointes” would be an important potential risk;
• When neutropenia is a listed adverse reaction, “serious infections” can still be classified as an
important potential risk even if there is not yet enough clinical evidence of serious infections
associated with neutropenia.
• When there is a high likelihood of off-label use and a safety issue has been identified as
derived from such use, if this risk is not already an important identified or potential risk for the
target population (GVP Module V Section V.B.5.8.), the specific risk should be included as an
important potential risk. Whenever possible, its name should be specific.
• For example, “severe bleeding [in off-label paediatric use]” should be used rather than
the unspecific term “off-label use in children” if bleeding is not already included as an
important identified or potential risk.