The recording and reporting of SUSARs is a cornerstone of the global continuous safety monitoring system which protects subjects participating in clinical trials from unknown or yet undocumented risks potentially linked to new investigational drugs. SUSARs must be reported within a very short time period and be as accurately described as possible. Most importantly, the sponsor must make an early determination whether the suspected adverse reaction is potentially related to the study drug and if it can be considered expected or not. An independent adjudication committee may be the best way to perform this assessment.
The evaluation of the safety of an investigational or marketed medicinal product is an evolving process. Available data depend on the stage of development:
- All available safety information on approved products is reflected in product labelling (and described in the Package Insert).
- Up-to-date safety information on the products under investigation is found in the Investigator’s Brochure (IB). This includes information gathered during In vitro testing and Nonclinical pharmacology/toxicology studies and any Clinical safety and pharmacokinetic data that may be available from earlier clinical studies (IBs are regularly reviewed and updated by sponsors). In short, for products under investigation, the IB is equivalent to the Package Insert.
Safety monitoring revolves around the identification, description, recording and reporting of Adverse Events (AE) that can be further categorized in various ways1:
- Unexpected Adverse Events
- Laboratory Abnormalities
- Adverse Events of Special Interest
- Common Adverse Events
- Rare Adverse Events
- Serious Adverse Events
- Adverse Reactions
Investigators are in the frontline of AE reporting and are the first to make an evaluation of the nature, severity, seriousness and relation to the study drug. They are advised to be consistent and to use scientific terminology when reporting Adverse Events as failing to do so may lead to confusion, incorrect or inadequate coding and ultimately may cause a safety signal to be missed.
A Serious Adverse Event (SAE) is any Adverse Event that results in the opinion of the Investigator or Sponsor in:
- Death or is life-threatening (immediate risk of death)
- Hospitalization or prolongation of existing hospitalization
- Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions (aka disability)
- Congenital anomaly / birth defect
- Other medically significant event
Investigators are required to report all SAEs to the Sponsor within 24 hours of being made aware of the event and appropriate channels are in place to allow this. The requirement is clearly described and documented in the training delivered to the sites by the sponsor.
Once an SAE report is received by the Sponsor, there needs to be a determination of whether the event should be considered a SUSAR. If so, the Sponsor has 15 calendar days to report it to the Health Authorities (7 days if the event is fatal or life-threatening). This allows Health Authorities to detect safety signals early on and take appropriate action such as order a halt in the study or request additional investigations.
The flowchart below describes the sequence of events starting with the occurrence of an AE. Once the Investigator has made the judgement about seriousness and relation to the study drug, the case is communicated to the Sponsor. It is now up to the Sponsor to determine whether the event is a SUSAR and to trigger an expedite reporting process.
Figure 1 Flowchart of SURAR reporting
What should be considered an Unexpected Adverse Event?3 Any Adverse Event that fulfills the following conditions should be considered as unexpected:
- Not listed in the Investigator’s Brochure (IB) or if IB not available or required
- Not listed at the specificity or severity observed
- Mentioned in IB as anticipated due to pharmacokinetic properties of the drug or occurred with other drugs in this class, but not with the study drug
In most cases the determination does not pause a particular challenge and the Sponsor can immediately initiate the collection of additional information regarding the AE and prepare the expedite reporting. However, it may happen that the case is complex and needs to be reviewed by an independent committee (Safety Monitoring Committee or Clinical Event Adjudication Committee). In such a case, it is imperative that a system be in place allowing for speedy review and documentation of the Committee’s opinion. Software platforms such as those used for Clinical Endpoint Adjudication can be a good solution as they incorporate all the necessary mechanisms, are compliant with regulations and offer features such as automated Audit Trail and Record Retention capabilities. If such a platform is already in place, it is the ideal tool for a SUSAR determination. This possibility should be considered when taking the decision whether to set up or not an electronic endpoint adjudication system for a clinical trial.
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1Presentation by Yuliya Yasinskaya, MD, Medical Officer, Center for Drug Evaluation and Research (CDER)
2Clinical Trial Safety Reporting requirements, SME info day 20 Mar 2017. Presented by Sophia Mylona, Clinical & Non-clinical Compliance , European Medicines Agency
321 CFR 312.32(a)
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