Reference safety information in clinical trials

The Reference Safety Information (RSI) shall be a part of the clinical trial application for all Investigational Medicinal Products (IMPs) and can be attached in two ways:

• In the Investigator’s Brochure (IB)
• In the Summary of Product Characteristics (SmPC)

The cover letter shall detail where in the clinical trial application the RSI can be found.

RSI in the Investigator’s Brochure

If the RSI is placed in the IB, there shall be a section with a clear listing of all expected serious adverse reactions. These are presented in a tabular format, including information concerning adverse reaction type, severity and frequency. 

If the IMP is to be studied concerning several different indications, it is appropriate to present a separate table per indication concerning expected adverse reactions. This is to avoid misinterpretation of data, e.g. oncological versus immunological indication for a particular IMP.

If the IB is more than one year old, this shall be justified in the application cover letter.

RSI in the Summary of Product Characteristics

If the RSI is placed in the SmPC, the listing of all expected adverse reactions shall be placed in section 4.8, which describes undesirable effects of the medicinal product. Please note that relevant safety information may be found in other sections as well, such as section 4.3 “Contraindications” and section 4.4 “Special warnings and precautions for use”.

If the IMP has a marketing authorization in several EU member states and there are several versions of the SmPC, the most appropriate SmPC to cover the safety of the included subjects in the current trial should be chosen.

Substantial amendments of the RSI

All modifications of the RSI are considered a substantial amendment to the clinical trial and must be justified based on available data. When amendments to the RSI are suggested these changes must be clearly indicated in a table with the Word function “track changes”.

When a substantial amendment concerning the RSI is submitted to the Swedish Medical Products Agency/Clinical Trials Information System (CTIS) it must be clearly indicated in the cover letter that the RSI has been updated, and where these changes can be found.

If the RSI is updated prior to the end of the period or the yearly Development Safety Update Report (DSUR), a detailed explanation of the data supporting the RSI update is required.

The Swedish Medical Products Agency therefore recommends that the RSI be updated in conjunction with the DSUR, which can then be used to support the update.

Guidance document regarding RSI, SUSAR and DSUR

The RSI lists all known serious adverse reactions and this information is used to determine if adverse reactions during a current trial should be reported as a Suspected Unexpected Serious Adverse Reactions (SUSARs) to the common EU database EudraVigilance.

A harmonisation group within the EU, with representatives from clinical trial units at the National Competent Authorities, Clinical Trials Facilitation and Coordination Group (CTFG), has developed a guidance document regarding reference safety information, reporting Suspected Unexpected Serious Adverse Reactions (SUSARs) and annual safety reporting in clinical trials.

Since 1 January 2019, the EU National Competent Authorities are advised to implement this guidance more strictly, and submission of an application and/or substantial amendment with an RSI that does not comply with the guidelines outlined in the Q&A document risks being rejected.

Covering note to CTFG guidance document RSI, Q&A

CTFG guidance document RSI, Q&A

ICH guideline E2F - Note for guidance on development safety update reports: