Reference Safety Information in Clinical Trials
The Reference Safety Information (RSI) section of an Investigator’s Brochure (IB) is an important document that can be a subject of audits and regulatory inspections.
In this post, I have provided guidance for some common questions regarding the RSI.
The Reference Safety Information (RSI) section of an Investigator’s Brochure (IB) is a list of expected serious adverse reactions (SARs), which are classified using Preferred Terms (PTs) as per the Medical Dictionary for Regulatory Activities (MedDRA).
The RSI should include a clear list of ‘expected SARs’ to the IMP(s).
Why do we need the RSI?
The RSI is used for the assessment of the expectedness of all ‘suspected’ serious adverse reactions that occur in clinical trials.
The Sponsors are required to conduct an expectedness assessment on each ‘suspected’ SAR for the following reasons:
- Determination of the expedited reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs), And
- Identification of SUSARs in the cumulative summary tabulation of ‘suspected’ SARs in the Development Safety Update Report (DSUR).
How should the RSI section be presented in the IB?
The RSI should be in a separate section titled “Reference safety information for assessment of expectedness of serious adverse reactions”.
The RSI section should be clearly identified within the IB and can be located within or close to section ‘Summary of Data and Guidance for the Investigator.
The Sponsor should ensure that the section of the IB that is used as the RSI is identified in the cover letter of the clinical trial application.
It should be clearly mentioned that the RSI section outlines expected SARs for regulatory reporting purposes and that the information within the RSI section does not present a comprehensive overview of the safety profile of the IMP(s).
How to determine which RSI version is applicable for expectedness assessment?
The approved version of the RSI (by the regulators – e.g., MHRA, UK) at the moment of occurrence of the SUSAR should be used. The RSI version should not be applied from case receipt date. The SARs may be reported late by the Investigator or identified late through monitoring; therefore, the onset date should be used to determine which RSI version is applicable for expectedness assessment, and this should not change when follow-up information is received.
Hence, the RSI used for expectedness assessment should be the one that has been approved by the regulators (e.g. MHRA, UK) and implemented by the organisation at the time of onset of the SAR.
What is the method of presentation of the frequency of expected SARs in the RSI?
One method that you can consider is to use the frequency categories as per the Council for International Organizations of Medical Sciences (CIOMS) recommendations. These are mentioned below:
|≥1/10 (> 10%)
|≥1/100 to <1/10 (> 1% and < 10%)
|≥1/1,000 to <1/100 (> 0.1% and < 1%)
|≥1/10,000 to <1/1,000 (0.01 % and < 0.1 %)
|<1/10,000 (< 0.01%)
However, if the number of the subjects exposed to the IMP are insufficient to use the above-mentioned categories (as may be observed during the early stages of clinical development), the number of observed ‘suspected SARs’ for each ‘expected SAR’ should be provided, together with the number of patients exposed.
What should be the format of the presentation of the RSI in the IB?
A tabular presentation can be used.
The nature of the ‘expected SARs’ must be listed by body system organ class and using preferred terms (PTs) as per the latest MedDRA version, followed by the frequency which is calculated on an aggregated level and based on what is previously observed ‘suspected’ SARs to the IMP.
An example of a hypothetical RSI table is mentioned below:
|Serious Adverse Reactions for the IMP considered expected for safety reporting purposes
|System Organ Class (SOC)
|Serious Adverse Reactions (SAR)
|Number of subjects exposed (N) = 400
|All SARs n# (%)
|Occurrence of fatal SARs n# (%)
|Occurrence of life- threatening SARs n# (%)
|Preferred Term 1
|Preferred Term 2
|Preferred Term 3
In scenarios where the IMP is under development for different medical indications, separate tables of expected SARs by indications may be appropriate, if the expected SARs are different (e.g., for oncology conditions and non-oncology indications).
The Sponsor should justify this approach in a cover letter of the clinical trial application.
What about presentation of fatal and life-threatening ‘suspected’ SARs in the RSI?
Generally, Sponsors should not expect an IMP to cause fatal SARs. Life-threatening SARs should not be considered expected for IMPs, unless supported by a positive benefit-risk balance.
Therefore, fatal and life-threatening SARs should usually be considered unexpected even if previous fatal and life-threatening SARs have occurred.
The listing of life-threatening or fatal SARs in the RSI of an IB indicates that the Sponsor expects the IMP to cause these SARs at this level of severity (as the RSI should only contain expected SARs).
In some cases, the listing of life-threatening SARs in the RSI could be acceptable, if a robust justification is provided.
If the Sponsor decides to add a fatal and/or a life-threatening SAR to the RSI section of an IB, an update of the benefit/risk statement for clinical trial subjects should be provided and adequate risk minimization measures should be proposed in the updated clinical trial protocol(s).
If the RSI section of an IB does include life-threatening and/or fatal expected SARs, the number of life-threatening (as assessed by the Investigator) and fatal ‘suspected’ SARs that have previously occurred must be given in the RSI. The number of all other life-threatening (as assessed by the Investigator) or fatal ‘suspected’ SARs that have occurred and that are considered unexpected and need to be reported should be listed elsewhere in the IB. It is recommended to provide this information either in a subsection on Safety under ‘Effects in Humans’ or in the section ‘Summary of Data and Guidance for the Investigator’.
- Clinical Trial Facilitation Group CTFG. Q&A document – Reference Safety Information. CTFG November 2017
- Reference Safety Information for Clinical Trials – MHRA Inspectorate. Weblink: https://mhrainspectorate.blog.gov.uk/2016/03/02/reference-safety-information-for-clinical-trials/
- A GUIDELINE ON SUMMARY OF PRODUCT CHARACTERISTICS (SmPC). September 2009. EUROPEAN COMMISSION
- Guidelines for Preparing Core Clinical-Safety Information on Drugs. Second Edition. Report of CIOMS Working Groups III and V. 1999
About the author
Dr. Sumit Verma MBBS MD, DNB
Director & Sr. VP, Global PV Operations
Dr. Sumit Verma is a medical graduate with specialization in anesthesiology and has more than 15 years of experience in the pharmaceutical industry, clinical medicine, clinical research, and pharmacovigilance. He has built teams that have consistently delivered and exceeded customer expectations across various pharmacovigilance domains that include case processing, signal management, risk management, aggregate reports, and clinical safety. He has co-authored two books – one on pharmacovigilance and another on pharmacology.
About Soterius: Soterius is a global industry leader in providing comprehensive drug safety and medical affairs services. We are a customer-focused organization, with a proven commitment to finding solutions for the people it serves, to driving excellence in compliance, and to improving patient outcomes. Soterius has its headquarters in New Jersey and offices in North America, Europe, and Asia. Our team has worked with some of the top global corporations across the world, handling diverse regulations and requirements. We are passionate about finding solutions and providing excellent quality services to our clients. Our quality systems are compliant, we are 24×7 available and always inspection ready.