Preparing the Reference Safety Information for a Clinical Trial

What are the steps that companies need to take when preparing the reference safety information for a clinical trial?  This article looks at the steps that you need to take.

What is Reference Safety Information?

Reference Safety Information (RSI) defines which reactions that are expected for the Investigational Medicinal Product (IMP) being administered to subjects participating in a clinical trial.

Q&A Document

The Clinical Trial Facilitation Group (CTFG) has updated the Q&A document on Reference Safety Information (RSI) following detailed discussions between national competent authorities and sponsors, which arose from the Clinical Trial application and substantial amendment procedures as well as GCP inspections. While the sponsor may use an approved Summary of Product Characteristics (SmPC) as RSI, it is more common that this information is provided in an Investigator’s Brochure (IB) for Investigational Medicinal Products (IMPs). The RSI in the IB cannot be regarded the same way as the undesirable effects listed in the SmPC, as pharmacovigilance rules for post-marketing and safety monitoring and reporting rules for clinical trials are significantly different as are the purpose and means of approval of the IB and SmPC.

What You Need To Know About Using RSI in Clinical Trials:

  • The primary purpose of the RSI, when used in clinical trials, is to serve as the basis for expectedness assessments of suspected serious adverse reactions for expedited reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) and annual safety reporting. Thus the RSI section of the IB should only contain expected Serious Adverse Reactions (expected SARs) to the Investigational Medicinal Product(s). It should be emphasized that a broader description of the safety profile of the IMP in addition to the RSI, e.g. tabular presentations of all observed adverse reactions (i.e. including non-serious adverse reactions, suspected SARs that have occurred only once, and fatal and life-threatening SARs that are considered unexpected and not included in the RSI), should be included elsewhere in the IB.
  • The RSI is a list of expected serious adverse reactions, which are classified using Preferred Terms (PTs) according to the Medical Dictionary for Regulatory Activities (MedDRA). An expectedness assessment is required to be conducted by the sponsor on each ‘suspected’ SAR to determine expedited reporting of suspected unexpected serious adverse reactions (SUSARs), and for the identification of SUSARs in the cumulative summary tabulation of SUSARs in the Development Safety Update Report (DSUR).
  • The content of the RSI should include a clear list of expected SARs to the IMP(s). These should be restricted to suspected SARs that were previously observed where, after a thorough assessment by the sponsor, reasonable evidence of a causal relationship between the event and the IMP exists.
  • In general, each expected SAR should also have been reported as a suspected SAR more than once. Suspected SARs that have occurred once cannot usually be considered expected, unless there is a very strong plausibility of a causal relationship with the IMP and a robust justification based on medical judgement is provided. Importantly, the occurrence of a suspected SAR on more than one occasion is not per se adequate justification for the addition of the term to the RSI as an expected SAR.
  • The list of expected SARs should be based on suspected SARs that were previously observed and not on the basis of what might be anticipated from the pharmacological properties of a medicinal product or the compound class (see section 2.C of the note for guidance ICH E2A).
  • As a general rule, 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. Fatal SARs can only be considered expected for IMPs with a MA in the EU, when it is clearly stated in the table or list of ARs in section 4.8 of SmPC that the IMP can cause these fatal SARs. Thus, the RSI of a product that has not received a MA in the EU should never include fatal SARs.
  • If the sponsor prepares an IB for the IMP(s) in a trial, the RSI should be contained in the IB in a clearly-identified separate section titled “Reference safety information for assessment of expectedness of serious adverse reactions”.
  • The RSI of an IMP with a marketing authorisation in the EU can be the table or list of ARs in section 4.8 ‘Undesirable Effects’ of the appropriate Summary of Product Characteristics (SmPC). This approach is acceptable if the IMP is used within the terms of the marketing authorisation.
  • The RSI should be presented in the form of a table, where 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 must be calculated on an aggregated level and based on previously observed suspected SARs to the IMP.
  • The frequencies of the expected SARs listed in the RSI are preferred to be in categories in analogy to the recommendation for the SmPC (section 4.8.) where possible (i.e. Very Common, Common, Uncommon etc.; for details see also ICH E2C(R2)). If there is an insufficient number of subjects exposed to the IMP to use these categories (e.g., during the early stages of product development), the number of observed ‘suspected SARs’ for each ‘expected SAR’ should be provided, together with the number of patients exposed.
  • If there are multiple lower level terms (LLTs) within a single PT they are all expected (for example if the PT hypophosphataemia is included in the RSI table, then the LLT hypophosphatemia is also considered expected). A product that is known to cause immunosuppression may also lead to infections, however only the PTs of the type of infections that have been observed should be considered expected, i.e. all infections cannot be considered expected.

The following safety information should not to be included in the RSI section of an IB, but should be presented elsewhere in the IB:

  • AEs considered unrelated to the IMP
  • Serious adverse events (SAEs) that were considered unrelated to the IMP
  • Non-serious ARs
  • Fatal suspected SARs that are considered unexpected and need to be reported as SUSARs, unless they are included in section 4.8 of the correspondent EU SmPC
  • SAR that have occurred only once, unless there is a very strong plausibility of a causal relationship with the IMP
  • SARs that are expected for similar products within the therapeutic class
  • Deaths or SAEs also considered efficacy endpoints in trials with high mortality
  • There may be situations where there the IMP is not expected to cause any SARs. For example – early in the clinical development of an IMP when subject exposure is low. In these cases, a clearly defined section of the IB called RSI should still be present, followed by a brief text stating that no SARs are considered expected by the sponsor for the purpose of expedited reporting and identification of SUSARs in the DSUR for the IMP.
  • A substantial amendment is always required to be submitted if there are changes to the RSI.

Our Advice

The preparation of the RSI for a clinical trial is not always a simple process and can be problematic, especially for un-marketed IMPs and those for which there is little early exposure data. We recommend that organisations undertaking clinical trials ensure that the primary purpose of the clinical trial RSI is served (expectedness assessments of suspected serious adverse reactions) and that the RSI section of the IB is detailed and thorough enough to allow the Investigator to fulfil his/her reporting obligations.

You can read the CTFG Q&A document in full on the HMA website.

If you would like to talk to us about clinical trials for your product or any other regulatory issue, then contact us by email: or call us on 00353 52 61 76706.  Alternately, you can complete the form below and we will get back to you.

Further Reading: Clinical & PV Articles

What Are Post-Marketing Surveillance Studies?

Post-marketing surveillance studies are defined in  Article 1(15) of Directive 2001/83/EC as studies carried out after a medicine has been authorised to obtain further information on a medicine’s safety or to measure the effectiveness of risk-management measures.  In this article, our Medical Manager, Dr. Danica Cvetkovic, looks at post-marketing surveillance studies and the link with Risk Minimisation Plans (RMP’s)

Read the article here.

Pharmacovigilance of Medicines for Rare Diseases

Dr. Danica Cvetkovic looks at the issue of pharmacovigilance for orphan or rare diseases.  Many issues associated with the sector are challenged by the small patient population. This article looks at the commonly used strategies for evaluation of post-approval safety and the effectiveness of rare and orphan drugs.

Read the article here.

Veterinary Clinical Trials: New EU Law & Global Approaches

Clinical studies are intended to advance animal health care by identifying the most effective therapies and practices for a given condition, or by advancing our basic understanding of the disease. Much like a clinical study in the human population, a veterinary clinical study involves research that gains information from animal patients.

Read the article here.

Download Our Clinical Trials E-Book

Acorn Regulatory is a leading regulatory, pharmacovigilance and clinical consultancy company headquartered in Ireland.  Our Clinical & Medical team works with the largest and the leading companies in life sciences to assist them in bringing their products to market.  The team, led by Dr. Danica Cvetkovic, has written extensively on the issue.  In the latest e-book from Acorn Regulatory, we look at the best and most popular articles from our Clinical & Medical team.

Download the e-book here.

About the Author
Gemma Robinson, PhD
Managing Director
As Managing Director of Acorn Regulatory, Gemma Robinson is actively involved on client projects on a day to day basis and she leads a team of respected pharmaceutical, medical device, pharmacovigilance and clinical trial experts.  Gemma is also an active contributor to developing and promoting standards in the regulatory affairs profession and she has worked with a number of academic and not for profit organisations to encourage individuals to pursue a career in regulatory affairs and the broader STEM subjects. You can read more articles by Gemma by clicking the link below.
Other articles by Gemma Robinson PhD