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In this article, we will see What is Safety concern, Identified risk, Potential risk and Missing Information.
Safety concern
An important identified risk, important potential risk or missing information.
The safety concerns of a medicinal product are identified, characterised, and monitored in the DSUR; the RMP, and in the PSUR / PBRER.
The ICH-E2E Guideline (see GVP Annex IV) uses the terms safety issue and safety concern interchangeably with the same definition for safety concern as defined in the ICH-E2C(R2) Guideline.
Identified risk
Definition according to GVP Annex I (Rev 3):
An untoward occurrence for which there is adequate evidence of an association with the medicinal product of interest.
Explanatory wording provided in GVP module V (Rev 2):
Undesirable clinical outcomes for which there is sufficient scientific evidence that they are caused by the medicinal product.
Identified risks can arise e.g. from signal evaluation and are described and classified (i.e., important or not important) in the PSUR / PBRER.
Identified risks have usually been observed in clinical trials or in clinical practice and are described in the SmPC. The causal relationship is already documented.
Examples:
- An adverse reaction adequately demonstrated in non-clinical studies and confirmed by clinical data;
- An adverse reaction observed in well-designed clinical trials or epidemiological studies for which the magnitude of the difference, compared with the comparator group on a parameter of interest suggests a causal relationship;
- An adverse reaction suggested by a number of well-documented spontaneous reports where causality is strongly supported by temporal relationship and biological plausibility, such as anaphylactic reactions or application site reactions (see ICH-E2F Guideline, Volume 10 of the Rules Governing Medicinal Products in the EU).
In a clinical trial, the comparator may be placebo, an active substance or non-exposure.
Adverse reactions included in section 4.8 of the summary of product characteristics (SmPC) are also considered identified risks, unless they are class-related reactions which are mentioned in the SmPC but which are not specifically described as occurring with this product (these would normally be considered as a potential risk)).
Potential risk?
Definition according to GVP Annex I (Rev 3):
An untoward occurrence for which there is some basis for suspicion of an association with the medicinal product of interest but where this association has not been confirmed.
Explanatory wording provided in GVP module V (Rev 2):
Undesirable clinical outcomes for which there is scientific evidence to suspect the possibility of a causal relationship with the medicinal product, but where there is currently insufficient evidence to conclude that this association is causal.
Potential risks have not necessarily been observed in clinical trials or in the clinical practice; however, preclinical or clinical considerations point to a possible causal association to the medicinal product.
Potential risks can be identified e.g. from signal evaluation and are described and classified (i.e., important or not important) in the PSUR / PBRER.
Examples:
- Non-clinical toxicological findings that have not been observed or resolved in clinical studies;
- Adverse events observed in clinical trials or epidemiological studies for which the magnitude of the difference, compared with the comparator group (placebo or active substance, or unexposed group), on the parameter of interest raises a suspicion of, but is not large enough to suggest, a causal relationship;
- A signal arising from a spontaneous adverse reaction reporting system;
- An event known to be associated with other active substances within the same class or which could be expected to occur based on the properties of the medicinal product (based on ICH-E2F Guideline, Volume 10 of the Rules Governing Medicinal Products in the EU).
Important risk?
Definition according to GVP Annex I (Rev 3):
An identified risk or potential risk that could have an impact on the risk-benefit balance of the product or have implications for public health.
Explanatory wording provided in GVP module V (Rev 2):
The RMP should focus on the important identified risks that are likely to have an impact on the risk-benefit balance of the product. An important identified risk to be included in the RMP would usually warrant:
- Further evaluation as part of the pharmacovigilance plan (e.g. to investigate frequency, severity, seriousness and outcome of this risk under normal conditions of use, which populations are particularly at risk);
- Risk minimisation activities: product information advising on specific clinical actions to be taken to minimise the risk, or additional risk minimisation activities.
The important potential risks to be included in the RMP are those important potential risks that, when further characterised and if confirmed, would have an impact on the risk-benefit balance of the medicinal product.
- Important risks are identified, characterised, and monitored in the DSUR; the RMP, and in the PSUR / PBRER.
- To define the important risks of a medicinal product, the overall knowledge on the safety profile of a drug is evaluated (e.g., mechanisms of action, epidemiology of the populations exposed, risk factors or risk groups, preclinical, clinical and, if available, post-marketing experience).
Important identified risk and Important potential risk
An identified risk or potential risk that could have an impact on the risk-benefit balance of the product or have implications for public health.
What constitutes an important risk will depend upon several factors, including:
- The impact on the individual
- The seriousness of the risk
- The impact on public health.
Normally, any risk that is likely to be included in the contraindications or warnings and precautions section of the product information should be considered important.
Missing information
Definition according to GVP Annex I (Rev 3):
(Critical) gaps in knowledge about a medicinal product, related to safety or use in particular patient populations, which could be clinically significant.
Explanatory wording provided in GVP module V (Rev 2):
Gaps in knowledge about the safety of a medicinal product for certain anticipated utilisation (e.g. long-term use) or for use in particular patient populations, for which there is insufficient knowledge to determine whether the safety profile differs from that characterised so far.
- Missing information is identified, characterised, and monitored in the RMP and the PSUR / PBRER.
- Typical examples of missing information are the use of a medicinal product in pregnant and lactating women or in the paediatric population, if there are not adequate clinical studies in these patients. The decision on whether the lack of safety information in a specific population is critical (=missing information) is based on clinical considerations.