I would be grateful for advice on two points:

The MHRA website safety reporting (see http://www.mhra.gov.uk/Howweregulate...SUSARsandASRs/) 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.