Reference Safety Information in Clinical Trials

Recommendation

5-7 November 2024
Hamburg, Germany

GMP meets Development
GMP and FDA Compliance in Pharmaceutical Development and IMP Manufacturing

A new post, "Reference Safety Information (RSI) for Clinical Trials" has just been published on the MHRA Inspectorate blog. The post provides recommendations to improve safety reporting since the agency is still seeing unreported suspected unexpected serious adverse reactions (SUSARs) and absence of adequate risk mitigation measures due to incorrect use of the RSI.

What is the purpose of the Reference Safety Information (RSI)?

The RSI is used to determine the expectedness of a Serious Adverse Reaction (SAR). If the serious event is considered related to the investigational medicinal product (IMP) and the serious reaction is not included in the RSI, this becomes a SUSAR and has to be reported to the MHRA. Inclusion of a SAR as an expected event in the RSI needs to be accompanied by an assessment of the benefit-risk profile of the IMP and ongoing trials. The competent authority will then decide whether the list of expected reactions and associated risk minimization measures are acceptable.

According to the agency, the purpose of the reporting obligation to national competent authorities (NCAs) is to:

• make them aware of SUSARs,
• collect information on the safety profile of an IMP,
• take appropriate actions to protect the safety of the trial participants.

Recent Inspection findings

The MHRA has listed common inspection findings, including the following:

• Incompliance regarding the Investigator Brochure (IB), e.g. delays in the implementation of updates,
• RSI version applied from case receipt date and not from onset date,
• Under-reporting of SUSARs for comparator products,
• Implementation of a substantial change prior to NCA approval,
• SARs in database listings with a fatal outcome incorrectly assessed as expected,
• SUSARs listed in the DSUR (Drug Safety Update Report) based on the extract from the safety database, which may have expectedness assessments based on a version of the RSI different from that approved at the beginning of the reporting period,
• Causality assessment has not been maintained by organizations when reviewing SARs,
• Frequency of expected SARs not indicated.

In addition, at the end of the post, the MHRA Blog provides useful tips to improve compliance (e.g. tracking of RSI updates, performing of impact assessments and compliance reviews).

For more information please read the MHRA Post Reference Safety Information (RSI) for Clinical Trials- Part III on the MHRA Inspectorate Blog.