The Reference Safety Information (RSI) in Clinical Trials has been one of our favorite topics since we started this blog. I first wrote about it in January 2018 after the Clinical Trials Facilitation Group (CTFG) issued their guidance document entitled “Questions and Answers – Reference Safety Information (RSI)”. In addition to presenting the main points of the guidance, I provided an overview of the background and the issues raised by MHRA Inspectors on this topic (1).
The CTFG guidance was a major step forward, which brought clarifications on many aspects to set the regulatory expectations for future inspections. Recognizing that this was a significant change, European Authorities announced a 1-year transition period in a Cover Note and that the new requirements would only be enforced from 01-Jan-2019, which led me to write about it again in April 2018 (2).
In addition to its many benefits, the CTFG guidance also brought new challenges, in particular regarding the date of implementation for the assessment of expectedness for suspected Serious Adverse Reactions (SARs), which defines if a case is a SUSAR that qualifies for expedited submission. For companies running multiple Clinical Trials in multiple territories, it became critical to identify which version of the RSI should be used for SUSAR and DSUR reporting activities.
The MHRA experience so far…
It has now been more than 2 years since the CTFG guidance became applicable and the MHRA GCP Inspectors continue to see non-compliance in this area. As described in a new post on the MHRA Inspectorate Blog (3), the GCP inspectors have raised Critical Findings related to this topic for 8 organisations since 01-Jan-2019.
The MHRA Blog Post provides a list of common findings the inspectors continue to observe and includes recommendations to improve compliance. I encourage everyone to read the MHRA piece but I would like to highlight the following points:
- Reminder: The MHRA must approve the RSI and any changes via a substantial amendment. There must be a good rationale to include a SAR in the RSI, and appropriate risk mitigation measures should be in place.
- Onset date: The assessment of SARs expectedness should be based on the RSI valid at the time of occurrence, including for follow-up information, as opposed to Case Receipt Date.
- Comparator IMPs: the comparator SmPC should be reviewed periodically to evaluate the need for protocol amendment and/or re-consent.
- Fatal and Life-Threatening SARs: Although there might be exceptions, this type of events should not be considered expected. Auto-labelling systems may fail to consider event severity, which would then result in unreported SUSARs.
- RSI implementation date: The RSI must be approved at a trial level. Furthermore, in a trial conducted in both the UK and the EU, it must be approved by both the MHRA and all concerned EU authorities. As a tip, the MHRA considers that it can be useful to have trial-specific RSIs.
- RSI for a licensed product: It is generally not acceptable to copy and paste section 4.8 of the SmPC into the RSI section of an IB.
- Lack of Efficacy and Disease Progression: SARs due to lack of efficacy or disease progression should not be considered expected, unless this has been approved as part of the protocol and/or in the RSI.
- MedDRA terms and updates: A process must be in place to assess whether MedDRA updates have an impact on the RSI.
In connection with this Blog Post, the MHRA has also published a new GCP Inspections metrics report (4), which covers inspections conducted from April 2018 to March 2019.
The report provides details about the 7 Critical Findings identified during inspections of Commercial Sponsors, which includes 2 Findings over Pharmacovigilance deficiencies: Critical Findings N°1 and N°5 both relate to deficiencies in the management of Reference Safety Information (RSI), which led to non-compliance with SUSAR and DSUR reporting requirements.
Based on the information presented in the Blog Post, we can expect to see more RSI Findings in the next GCP Inspections metrics report. So… Watch this space !!
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(1) Safety Observer article – “RSI in Clinical Trials: The EU Guidance explained”, 04-Jan-2018: Link here
(2) Safety Observer article – “RSI in Clinical Trials: EU Authorities set Compliance Date”, 20-Apr-2018: Link here
(3) MHRA Inspectorate Blog article – “Reference Safety Information (RSI) for Clinical Trials- Part III”, 05-Feb-2021: Link here
(4) MHRA GCP Inspections Metrics Report – Period from April 2018 to March 2019, 12-Feb-2021: Link here