Things you need to understand about Reference Safety Information
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 (CTs).
Major and critical findings related to pharmacovigilance are often raised during regulatory inspections and the root cause for these finding is normally linked to the management of the RSI across the different stakeholders’ groups.
RSI in a clinical trial, is the information used for assessing whether an adverse reaction is expected. This is contained in a clearly separated specific section within the Investigator’s Brochure (IB) for IMPs that do not have a marketing authorization (MA), or in the section “Undesirable Effects” of the Summary of Product Characteristics (SmPC) for IMPs with a MA which are used according to the MA.
The RSI in a clinical trial should be a list of medical events that defines which reactions are expected for the Investigational Medicinal Product (IMP) and their frequencies. Generally, the sponsor will perform the assessment of expectedness. These ‘expected SARs’ should be restricted to ‘suspected’ SARs that were previously observed more than once, where, after a thorough assessment by the sponsor, reasonable evidence of a causal relationship between the event and the IMP exists.
RSI is one single definitive list or document that determines which SARs require expedited reporting to the relevant National Competent Authority and which are exempt.
The RSI should be presented in the form of a table, where the nature of the ‘expected SARs’ must be listed by MedDRA body System Organ Class (SOC) and Preferred Terms (PTs) followed by the frequency. The latest MedDRA version should always be used.
The RSI used for a clinical trial, against which expectedness assessments are made, should be clearly identified in the protocol. Protocols often lack clarity on this, stating only that the SmPC or IB is to be used.
The sponsor’s Quality Management System (QMS) should also define what the RSI is or how it is maintained and implemented.
At the start of the trial, checks should be made to ensure that the risks and side effects listed in the subject information sheet given to trial subjects are consistent with those listed in the IB and/or SmPC.
Changes on the IB or SmPC do not mean that the RSI changes, but any change to the RSI represents a substantial amendment. Therefore, the new RSI cannot be implemented and used to assess expectedness until the amendment has been approved.
It is quite often raised by Regulatory Authorities during Sponsor GCP inspections that new versions of the RSI are implemented for expectedness assessment before regulatory approval.
If the trial is international, the RSI should be consistent in all the territories where the trial is taking place. The standard approach is that the same RSI is used across the trial regardless of where trial sites are based for uncomplicated safety reporting. In case of changes, for example, the updated IB is normally put on hold until it is approved in all countries, to implement it in one go across the study.
Remember that you can now access our ICH GCP E6 (R2) for Investigators and Clinical Research staff online course below:
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REFERENCES
ICH E2A Clinical Safety Data Management: definitions and standards for expedited reporting.
Detailed guidance on the collection, verification and presentation of adverse event/reaction reports arising from clinical trials on medicinal products for human use (CT-3) (2011/C 172/01)
Clinical Trials Regulation (EU) NO 536/2014. Questions and Answers (7.7 – 7.20). Version 2.5. September 2020
MHRA Good Clinical Practice Guide, Medicinal and Healthcare products Regulatory Agency, UK
Reference Safety Information for Clinical Trials. MHRA Inspectorate Blog. B. Naeem, March 2016
Reference Safety Information II. MHRA Inspectorate Blog. B. Naeem, January 2017
Integrated Addendum to ICH E6 (R1): Guideline for Good Clinical Practice E6(R2). November 2016.
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Author: Dr Leire Zúñiga, Director and Principal GCP Consultant
PHARMITY, 29th of October 2020
