The Medicines and Healthcare products Regulatory Agency (MHRA) Inspectorate blog shares the inspection activities carried out by the agency. A third blog post on Reference Safety Information (RSI) for clinical trials has recently been released covering this aspect of pharmacovigilance.
RSI is a list of medical events which outline the expected reactions for the Investigational Medicinal Product that is the focus of the trial. The RSI is used to define expected Serious Adverse Reactions (SAR), and consequently what is a Suspected unexpected Serious Adverse Reaction (SUSAR) which must be reported to the MHRA. The Clinical Trials Facilitation and co-ordination Group (CTFG) have a Q&A document released at the end of 2017 which provided guidance on the issue. Sponsors were required to be compliant with the new requirements from this guidance from 01 Jan 2019. However, the MHRA has produced this latest blog to highlight the continued non-compliance with RSI requirements they have noticed through their inspections.
The blog post comprises the inspectors’ common findings along with recommendations on how to improve compliance
- CTFQ Q&A impact assessment – delays in the implementation of ensuring procedures and RSIs comply with the CFTG Q&A on RSI.
- Onset date – the RSI version used in the expectedness assessment of SARs should be based on the onset date and not case receipt date as SARs may be reported late or identified late through monitoring.
- Comparator IMPs – Under reporting of SUSARs for comparator products reinforces the requirements for comparator summary of product characteristics (SmPCs) to be periodically reviewed.
- Fatal and life-threatening (LT) SARs – these SARs should not be considered as expected unless explicitly stated in the approved RSI. Any of these events which are considered as expected should be re-assessed as unexcepted and unblinded for SUSAR determination and reporting.
- RSI implementation date – RSIs must be trial specific, even if an RSI is applicable to more than one trial, it must be approved for each individual trial before it can be used. In addition, RSIs conducted in both the UK and EU must be approved by both the MHRA and all competent authorities of EU member states.
- RSI for a licensed product – this can be the RSI section in the Investigators Brochure however copying and pasting section 4.8 of the SmPC will not be accepted.
- Lack of efficacy and disease progression – this should not be considered expected unless specifically approved as part of the trial protocol/is listed in the RSI. The protocol should clarify the approach to take regarding disease progression
- MedDRA terms and updates – description of expected reactions included in the RSI are recommended to be done using MedDRA preferred terms. A process of conducting a documented assessment on the impact of MedDRA updates on the RSI must be in place.
- Drug Safety Update Reports (DSURs) – the RSI used for the DSUR listings bust be the same RSI in place at the start of the reporting period. Additionally, when more than one RSI was used during the reporting period, this must be clear in the DSUR or the cover letter
- Frequency of expected SARs – A category of unknown frequency is not permissible. The acceptable categories are:
- Very common
- Very rare
- RSI for biosimilars/generics – all SARs caused by a biological medicinal product with an unproven biosimilarity to the reference product should be considered unexpected. There may be exceptions and this will be assessed on a case-by-case basis.
Whilst the list of common issues contains several suggestions on how to improve the RSI, there is a dedicated section at the end of the blog with tips on how to improve compliance. The main focus is on RSI updates, specifically submitting and tracking them. However, additional advice concerns the CTFG impact assessment, compliance reviews/metrics, DSUR review and the Investigator Brochures.
The full blog post can be found here.