Categorizing Risks
From a sponsor’s first authorization to conduct a clinical drug trial in any country worldwide, they must prepare and submit development safety update reports (DSURs) annually. The purpose of the DSUR is to present a comprehensive evaluation of safety information related to the sponsor’s investigational drug.1
A mandatory part of this safety evaluation is the development of the risk profile of an investigational drug, presented in the DSUR as important identified and potential risks. Per the regulations, sponsors need to correctly categorize their investigational drug risks. The table below provides the framework for these categorizations.
Categorizing Risks2
| Type of risk | Definition | Examples |
|---|---|---|
| Identified risks | Undesirable clinical outcomes for which there is sufficient scientific evidence that they are caused by the medicinal product. | Reports of adverse drug reactions (ADRs) may be derived from nonclinical findings confirmed by clinical data, clinical trials, epidemiological studies, and spontaneous data sources (including published literature). |
| Potential risks | Undesirable clinical outcomes for which there is scientific evidence to suspect the possibility of a relationship with the product, but where there is currently insufficient evidence to conclude that this association is causal. | This may include class risks. Note: where there is a scientific rationale that an ADR might be associated with off-label use, used in unstudied populations, or resulting from long-term product use, the ADR should be considered a potential risk. |
| Important identified risks | Identified risks that are likely to have an impact on the benefit-risk balance of a product or impact public health. | An important identified risk would usually warrant further evaluation to investigate the frequency, severity, seriousness, and outcome of this risk under normal conditions of use and determine which populations are at risk as well as associated risk minimization activities such as including information in the warnings and precautions sections of the drug label. |
| Important potential risks | Potential risks that, if confirmed, would have an impact on the benefit-risk balance of a product or impact public health. | An important potential risk would usually warrant further evaluation to investigate the frequency, severity, seriousness, and outcome of this risk under normal use and determine which populations are at risk. |
| Nonimportant risks | Risks that are not considered to be relevant for a product given therapeutic context. | These risks are either infrequent, non-serious, reversible, and/or readily managed with no significant impact on individual patients or public health. |
Managing Risks
Throughout an investigational drug’s development, a risk can be downgraded, i.e., from an important identified risk to an important potential risk, or from an important risk (identified or potential) to a nonimportant risk. Likewise, a risk can be upgraded from an important potential risk to an important identified risk. When the sponsor applies for marketing authorization of their investigational drug in the European Union, the final list of important risks in the DSUR forms the basis of the safety concerns in the risk management plan (RMP). This list can also inform the ‘Warnings and Precautions’ and/or ‘Contraindications’ sections of the product label.
As with the DSUR, the RMP is a dynamic document that should be updated throughout the lifecycle of the drug. As the safety profile is further characterized, this includes adding risks where required; risks may also be removed or recategorized.
The emphasis of the RMP is on the risks or the populations that need proactive management with risk minimization measures (e.g., labeling, educational material) or further study with pharmacovigilance activities (e.g., post-authorization safety studies).2
Whilst the RMP is the tool used to describe the risks and their management, it is the periodic safety update report (PSUR; also referred to as the periodic benefit-risk evaluation report [PBRER]) that is used to monitor and evaluate the risks at defined time points.
The PSUR/PBRER presents a critical analysis of new or emerging information on a drug’s risks and benefits that enables an appraisal of the drug’s overall benefit-risk profile. As product development continues, and as more experience is gained from postmarking safety data, the important identified risks and important potential risks are updated.
Ideally, the risks described in the DSUR, PSUR/PBRER, and RMP should align. However, in practice, as product development continues, and as the sponsor seeks marketing approval e.g., for additional indications or regions, the risks described in the RMP, DSUR, and PSUR/PBRER can become complex and, in some cases, disparate.
For example, as more countries grant marketing authorization, local health authorities, e.g., the European Medicines Agency and the Food and Drug Administration, may request keeping or removing risks from the RMP. This results in regional variations in the risks. This variation requires the development of country-specific RMPs and PSURs as well as the maintenance of a core RMP (stating the company’s core position).
Although some risks may be added to, or removed from, the RMP or PSUR through communication with health authorities, all of the risks for a marketed drug (including risks found in country variations and risks downgraded as nonimportant) are reviewed periodically in the PSUR for new information and assessed in the context of the cumulative information.3 Therefore, the PSUR includes the definitive list of risks (important and nonimportant) for a marketed product for all regions/countries globally with marketing authorization.
How we can help you meet these regulatory requirements
The Certara safety/pharmacovigilance writing team has over 60 years of cumulative experience writing aggregate safety reports. We can support your aggregate report writing needs and help you develop your drug’s risk management strategy. For more information about recent regulatory updates to DSURs, watch this webinar.
References
1. ICH guideline E2F on development safety update report Step 5. European Medicines Agency. September 2011. EMA/CHMP/ICH/309348/2008.
2. Guideline on Good Pharmacovigilance Practices (GVP) Module V – Risk management systems (Rev 2). European Medicines Agency. 28 March 2017. EMA/838713/2011.
3. Guideline on Good Pharmacovigilance Practices (GVP) Module VII – Periodic safety update report (Rev 1). European Medicines Agency. 09 December 2013. EMA/816292/2011.