As reported
in the December 2017 issue of Safety Observer, the Heads of Medicines Agencies
(HMA) have 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.
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: Link Here
- The issue was subsequently discussed with Industry representatives at the MHRA GCP Stakeholder Engagement Meeting (StEM) on 18-Mar-2016 : Minutes and Presentations on this Page
- This was presented at the MHRA GCP Symposium in September 2016: Link Here
- A second Blog Post was published in January 2017: Link Here
As
described in the EFPIA Position Paper published in September 2016 (Link Here),
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.
Here is a
list of the main requirements described in the new Q&As document (Link Here):
- 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 ?
Please feel
free to use the comment field at the bottom of this post to share your
experience or concerns, or to explain what the new guidance will change for
your company. Thank you !
Thierry is
also Chief Editor of Safety Observer, a provider of Regulatory Intelligence
services for Pharmacovigilance since 2005.
