RSI in Clinical Trials: The EU Guidance explained

As reported to our clients in December 2017, the Heads of Medicines Agencies (HMA) published a new version of their guidance document entitled “Questions and Answers – Reference Safety Information (RSI)”. This is a deliverable of the Clinical Trials Facilitation Group (CTFG), replacing the previous version dated December 2013.

The regulatory context and resulting issues

Until now, the relevant EU regulatory requirements were specified in the EU-CT 3 guideline published in June 2011 (1) and the above mentioned CTFG Q&As introduced in December 2013 (2).

Without going into too much detail, there were some gaps in this guidance and a number of companies received inspection findings for not meeting expectations in relation to the RSI, particularly in the context of SUSAR reporting.

As I have seen myself during audits, some companies merely included in their Investigator’s Brochure a list of all suspected ADRs observed during clinical trials, which they considered as the RSI. Needless to say that this did not help the clinical Investigator sites very much in getting familiar with the safety profile of the Investigational Medicinal Product (IMP).

Any new occurrence of an observed ADR was subsequently considered “expected” and no longer qualified for SUSAR reporting. Through this approach, the information necessary to monitor the safety profile of the IMP is only available to the Sponsor whereas the other stakeholders, including Authorities and Ethics Committees, are left in the dark, unable to fulfill their responsibilities with regards to subject protection.

Another aspect of the problem relates to the implementation of an updated RSI: As clearly specified in the existing guidance, a revised RSI should be submitted as a Substantial Amendment. What was not so clearly specified is that companies should not implement the updated RSI for expectedness assessment until it is approved by the Authorities.

As mentioned already, this has caused a number of Inspection Findings and companies have also seen some of their RSI Amendments rejected by the Authorities, in particular the MHRA.

The MHRA Inspectorate communicated about the issue, in an attempt to educate the Industry about their expectations:

• A first Blog Post was published in March 2016 (3)
• The issue was subsequently discussed with Industry representatives at the MHRA GCP Stakeholder Engagement Meeting (StEM) on 18-Mar-2016 (4)
• This was presented at the MHRA GCP Symposium in September 2016 (5)
• A second Blog Post was published in January 2017 (6)

As described in the EFPIA Position Paper published in September 2016 (7), the industry expressed some concerns with the implications of this issue and called for better guidance, which has now led to the publication of the updated Q&As document.

The New RSI Q&As: Key Take-Home Messages

One could challenge why this is not part of Eudralex Volume 10 but the important point is that new guidance is now available on the HMA website. The Q&As document has been expanded from 6 to 18 questions and from 3 to 19 pages to explain what information the RSI should include and how it should be presented. It includes clarifications on a number of rather technical aspects including the use of MedDRA terms, or the expression of frequency and severity of the events listed in the RSI. Moreover, it explains how it should be used in the context of applicable expedited (i.e. SUSAR) and periodic (i.e. DSUR) reporting.

Here is a list of the main requirements described in the new Q&As document (8):

• Question 1: The content of the RSI should include a clear list of “expected” Serious Adverse Reactions (SARs) for the IMP, based on thorough causality assessment of observed SARs. This is therefore a subset of all observed SARs for which the Sponsor can justify a very strong plausibility of a causal relationship and it would generally exclude SARs that have been observed only once.
• Question 11: A Substantial Amendment is always required to be submitted if there are changes to the RSI.
• Question 12: This Substantial Amendment should be submitted to the authorities in all EU Member States where trials are ongoing in parallel to the DSUR submission.
• Question 12: The updated RSI can only be used for assessment of expectedness of SARs after the approval of the Substantial Amendment in all Member States where trials are ongoing.
• Question 12: The identification of SUSARs in the “Cumulative summary tabulation of serious adverse reactions” in a DSUR should be based on the version of the RSI most recently approved in all Member States (Note that this may not be the version “in effect at the start of the reporting period” as specified in CT-3)
• Question 17: When the WHO classification categories are used for causality assessment, “unlikely” is considered “not related”.
• Question 18: The RSI used for the assessment of the initial SAR should be used to assess expectedness for follow up reports. SUSARs should not be downgraded even if the SAR became “expected” through an update of the RSI.

Where does this leave us ?

There is no doubt that the new guidance brings welcome clarifications on many aspects and the regulatory expectations are now clearly set for future inspections. It will also help many companies who did not know what information to include in the RSI or how to present it.

On the other hand, one of the concerns raised by the EFPIA was that companies consider the RSI as a global document. In order to comply with the new version of the Q&As and the requirement to make the RSI effective only after approval by all concerned EU member states, companies may need to use a different version of the RSI in Europe compared to other regions. Unfortunately we may not obtain the desirable harmonisation until the issue is discussed at ICH level.

Even within Europe, I know companies who are concerned by the potential delay it takes some authorities to approve Substantial Amendments, which I have heard can take up to 6 months even though the current guidelines specify a 35-Day response period…In this context, some companies have decided to use a “tell, wait and do” procedure, which is used by the EMA for some variations to a Marketing Authorisation: In the cover letter, the Sponsor informs the receiving authority that unless stated otherwise, the RSI will be considered effective after a period of 60 days. Does this sound like a reasonable compromise ?