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Thread: Reference Safety Information (RSI) - annual updates

  1. #1
    Forum Member
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    May 2012

    Reference Safety Information (RSI) - annual updates

    I would be grateful for advice on two points:

    The MHRA website safety reporting (see says that:

    Annual Investigators Brochure (IB) Update
    The Reference Safety Information (RSI) for any Investigational Medicinal Products (IMPs) involved in a clinical trial must stay consistent during each reporting period. At the end of the reporting period the sponsor may assess the new safety information that has been generated and submit any proposed safety changes to the IB or reference safety information as a substantial amendment. This amendment should be supported by the ASR/DSUR and approved before the RSI is changed.

    Changes to the reference safety information include the downgrading of reactions form unexpected to expected. Until the amendment justifying the downgrading has been approved the events must be treated as unexpected.

    • I understood from elsewhere that IB updates were only substantial amendments if they changed the risk/benefit assessment of the trial. Therefore there may be changes to the IB and/or downgrading of reactions from unexpected to expected that do not alter the risk/benefit assessment. Is this contradictory or have I misunderstood something?

    • I sometimes see ctIMPs using licensed medications and the SPC is the RSI. We currently assess expectedness against the current version of the SPC at the time of receipt of the event report. SPC updates are not done to specific timescales and may be updated within reporting periods. How do we handle updates of SPCs? We do not routinely monitor these against the risk/benefit assessment, but should we be doing this? Should we use one version and update the version in use say annually rather than using the version published at the time of event evaluation?

    Thanks for any advice on this.

  2. #2
    I'm afraid I can't answer your questions but I would be very much interested in any response. As a non-commercial CTU based within an NHS Trust, we have similar problems with updating reference safety information and the guidance isn't particularly helpful.

  3. #3
    Similar question. If the Pharmaceutical company have submitted the updated IB to the MHRA (as required) but deem that the changes to the RSI do not affect the risk/benefit assessment of our trial, as does the Chief Investigator, do we, the academic CTU using the IB, still have to submit the changes to the RSI in the IB as a substantial amendment as per the Grey Guide at a cost of 250?

  4. #4
    To help clairfy expectation, please see a response from the MHRA:

    RSI refers to the Reference Safety Information. This is a list of medical terms detailing the Serious Adverse Reactions (SARs) that are expected for the IMP which is to be used by investigators as a reference point when assessing a SAR to determine whether it is a SUSAR. It is not the entire IB or SmPC but rather a section within the document i.e. Section 4.8 Undesirable effects. IB or SmPC changes that do not alter the RSI and have no impact on Risk/Benefit do not need to be submitted to the MHRA as substantial amendments.

    Sponsors should be aware that any change to the RSI is a change to the Risk/Benefit and requires that a substantial amendment be submitted to the MHRA and approved before it is implemented in the trial. If you are a non-commercial sponsor using a IB provided by a Pharmaceutical company and they issue an update which contains RSI changes then you have two options. The first is to submit a substantial amendment to the MHRA to update your IB and change your RSI. The second option is to conduct and fully document a risk assessment of the changes and if you feel that you can justify not using the new RSI to again document it and continue with the old IB.

    If you are using the SmPC for your RSI then the assessment should be made against the version of the SmPC that was submitted with your initial application as this is your approved RSI. If a new version of the SmPC is released then you should conduct an assessment of the changes and make a documented decision as whether you need to update your RSI or continue with the old version of the SmPC. If you decide you do wish to change to the new version of the SmPC then you will be required to submit a substantial amendment to the MHRA.

    We hope this helps clarify expectations as sponsor.
    MHRA Super Moderator

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