Reference Safety Information in Clinical Trials

By Anne Lloyd

In March 2016, the Medicines and Healthcare products Regulatory Agency (MHRA) published a blog entitled ‘Reference Safety Information (RSI) for Clinical Trials’ having observed that this theme often led to inspection findings. A further blog was published in January 2017 to address some of the queries raised in response to the first blog. Despite these, and discussing the current issues seen in relation to the use and control of RSI at various meetings, the MHRA continued to see non-compliance, including unreported suspected unexpected serious adverse reactions (SUSARs) and an absence of adequate risk mitigation measures due to incorrect use of the RSI. They therefore published a further blog in February 2021.

Even though the Brexit transition period ended on 31-Dec-2020, the MHRA still accept the provisions of the CT-11 and CT-32 and the Clinical Trial Facilitation Group (CTFG) Q&A on RSI3. Therefore, they expect that they are followed, along with The Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1013 as amended)4, as that is their interpretation of how the legislative requirements can be met and will help in terms of harmonisation and running global trials. Organisations had until 01-Jan-2019 to ensure that their procedures and RSIs followed the CTFG Q&A on RSI by performing an impact assessment against the approved RSIs. It was expected that a retrospective review be performed and any unreported SUSARs identified be submitted and serious breaches be reported.

What is the RSI?

For clinical trials, the RSI should be the list of medical events that defines which reactions are expected for an Investigational Medicinal Product (IMP), whether it is the drug under investigation or a comparator. If a serious adverse reaction (SAR) is considered related to an IMP (suspected) and the SAR is not included in the RSI (unexpected), then this becomes a SUSAR and requires expedited reporting to the relevant National Competent Authorities (NCAs) and, for cases originating in the UK, to the Research Ethics Committees (ECs). It is important to remember that fatal and life-threatening SARs should not be considered expected, unless explicitly stated in the RSI and approved by the NCA. This includes all SARs with a fatal outcome. In a similar way, SARs due to lack of efficacy or disease progression, should not be expected unless they have been approved as part of the trial protocol or included in the RSI.

The RSI is used by the sponsor for identifying SUSARs and by the NCA to determine the continuing risk-benefit of the trial. The expectedness assessment is not a medical decision, and the RSI should include MedDRA preferred terms (PTs), which can be compared with the PTs the SAR has been coded to. However, the decision to include a SAR in the RSI section is based on medical assessment. There must be a good rational why a SAR is expected (e.g. biological plausibility, temporal association) and appropriate risk mitigation measures must be in place. The frequency of the expected SARs should be indicated using the Council for International Organisations of Medical Sciences (CIOMS) categories (very common; common; uncommon; rare and very rare). A frequency of not known is not acceptable because it does not allow assessment of whether the new SAR report represents an increased frequency and therefore is unexpected. If the frequency cannot be calculated, the number of SARs should be provided. The RSI can be a clearly defined section within the Investigators Brochure (IB) or section 4.8 of the Summary of Product Characteristics (SmPC), but they are not one and the same. This must be clearly defined and communicated to the people conducting the expectedness assessments to ensure that they are using the correct one.

If you have different RSIs for different regions, you need to make sure that all SARs are assessed against the RSI approved in the region where you are submitting the SUSARs, not the RSI from the region in which the event occurred.

Maintaining the RSI

The RSI and the process for managing and maintaining (including tracking the updates and monitoring compliance metrics) should be clearly defined within the sponsor’s quality system to enable the staff who are using and maintaining it are able to do so in a compliant manner.

The RSI needs to be part of the initial clinical trial application and once it has been approved it has to be used unless the regulator (e.g. the Clinical Trial Unit at the MHRA) agrees otherwise, which would require the sponsor to submit a substantial amendment to change it. if a trial is being conducted in both the UK and European countries, the RSI must be approved by all the NCAs where it is being performed. If you implement RSI without regulatory approval, then the regulator has not had the opportunity to: • Assess new information that may impact on the risk benefit ratio of the trial.

• Determine if, as a result of the information, your IMP and its dosing regime are still appropriate for the trial population. • Make an informed decision about the clinical trial authorisation.

If an RSI is applicable to more than one trial, and if an update is approved for one trial, it does not mean that the RSI can be used in the other trials before it has been approved by the NCA. However, you can submit the RSI update as a substantial amendment for all of the trials in the UK that it applies to, with a list of the trials in the cover letter, and the assessor will review the impact and issue an approval for them all in one go. You can also submit more than one amendment at a time, so you do not need to wait for a protocol/Investigational Medicinal Product Dossier (IMPD) update to be finalised before submitting the RSI update, as long as you make it clear in the covering letter what other submissions have been made and how they are linked. The RSI used must be the one approved on the onset

date of the SAR and this does not change if follow-up information is received. An update to the RSI does not allow you to downgrade all the old SUSARs. For the Development Safety Update Report, the RSI in place at the start of the reporting period must be used for all the DSUR line listings. If the IB or SmPC are updated, then a risk assessment should be performed of the new version against the current version. If there are no changes to the RSI or the changes are minimal or not relevant to the study or patient population, then you can choose to continue with the current RSI.

If you are using a clearly defined section of the IB as your RSI and have important new safety information that you want to communicate to your investigators, this can be done without sending them an unapproved IB. For example, sending out updated line listings or a dear doctor/investigator letter. If a new version of the SmPC is approved, this can be made available to those conducting the trial if those conducting the expectedness assessment clearly understand which version should be used as the RSI.

If there are new events listed as expected, then the substantial amendment must be sent, together with a covering letter explaining the rationale for the additional events, and the new RSI must not be implemented until approval is obtained. If the amendment is submitted mid DSUR period, the amendment should state that the new RSI will not be implemented until the end of the current DSUR period. 1. Communication from the Commission — Detailed guidance on the request to the competent authorities for authorisation of a clinical trial on a medicinal product for human use, the notification of substantial amendments and the declaration of the end of the trial (CT-1); https://eur-lex.europa.eu/legal-content/

EN/TXT/?uri=CELEX:52010XC0330(01). 2. Communication from the Commission — Detailed guidance on the collection, verification and presentation of adverse event/reaction reports arising from clinical trials on medicinal products for human use ( ‘CT-3’ ); https://eur-lex.europa.eu/legalcontent/EN/TXT/?uri=CELEX:52011XC0611(01). 3. Clinical Trial Facilitation Group (CTFG) Q&A document – Reference Safety Information, Nov-2017; https://www.hma.eu/fileadmin/dateien/Human_

Medicines/01-About_HMA/Working_Groups/

CTFG/2017_11_CTFG_Question_and_Answer_on_

Reference_Safety_Information_2017.pdf. 4. The Medicines for Human Use (Clinical Trials)

Regulations 2004, Statutory Instrument 2004 No. 1031 (as amended); https://www.legislation.gov.uk/ uksi/2004/1031/contents/made.

Anne Lloyd, FPIPA

PIPA Committee Member