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RSI for Clinical Trials

The Reference Safety Information (RSI) is used for the assessment of the expectedness of all ‘suspected’ serious adverse reactions (SARs) that occur in clinical trials. Therefore the RSI is a list of expected serious adverse reactions, which are classified using Preferred Terms (PTs) according to the Medical Dictionary for Regulatory Activities (MedDRA).

An expectedness assessment is required to be conducted by the sponsor on each ‘suspected’ SAR to determine expedited reporting of ‘suspected unexpected serious adverse reactions (SUSARs) and for the identification of SUSARs in the cumulative summary tabulation of ‘suspected’ SARs in the Development Safety Update Report (DSUR).

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What safety information should not be included in the Reference Safety Information of the Investigator’s Brochure?

The following safety information should not to be included in the RSI section of an IB, but should be presented elsewhere in the IB (e.g. in a table, preferably, located in the subsection on Safety under ‘Effects in Humans’ or in the section ‘Summary of Data and Guidance for the Investigator’, near the RSI section) if available:

  • Adverse events (AEs) that were considered unrelated to the IMP by both the investigator and the sponsor,
    Serious adverse events (SAEs) that were considered unrelated to the IMP by both the investigator and the sponsor,
    Non-serious ARs, Fatal ‘suspected’ SARs that are considered unexpected and need to be reported as SUSARs, unless they are included in section 4.8 of the correspondent EU SmPC, Life-threatening (as assessed by the investigator) suspected SARs that are not considered to be ‘expected’ SARs for the IMP and need to be reported as SUSARs.
  • SAR that has occurred only once, unless there is a very strong plausibility of a causal relationship with the IMP and a robust justification based on the medical judgment is provided.
  • Deaths or SAEs also considered efficacy endpoints in trials with high mortality or morbidity accepted in the authorized protocol by the competent authority to be treated as disease-related events and not subject to systematic unblinding. However, careful assessment should be performed in cases where disease-related events appear to be enhanced by the IMP. In accordance with CT-3 guidance, a causality assessment is required for each SAE, and if the investigator considers the disease-related event to be IMP-related and the event is serious then it must be reported as a SUSAR.
  • SARs that are expected for similar products within the therapeutic class, which did not occur in subjects taking the IMP.