RSI in Clinical Trials: MHRA Findings and Tips

The Reference Safety Information (RSI) in Clinical Trials has been one of our favorite topics since we started this blog. I first wrote about it in January 2018 after the Clinical Trials Facilitation Group (CTFG) issued their guidance document entitled "Questions and Answers – Reference Safety Information (RSI)". In addition to presenting the main points of the guidance, I provided an overview of the background and the issues raised by MHRA Inspectors on this topic: link here

The CTFG guidance was a major step forward, which brought clarifications on many aspects to set the regulatory expectations for future inspections. Recognizing that this was a significant change, European Authorities announced a 1-year transition period in a Cover Note and that the new requirements would only be enforced from 01-Jan-2019, which led me to write about it again in April 2018: link here

In addition to its many benefits, the CTFG guidance also brought new challenges, in particular regarding the date of implementation for the assessment of expectedness for suspected Serious Adverse Reactions (SARs), which defines if a case is a SUSAR that qualifies for expedited submission. For companies running multiple Clinical Trials in multiple territories, it became critical to identify which version of the RSI should be used for SUSAR and DSUR reporting activities.

Photo by Karla Hernandez on Unsplash

It has now been more than 2 years since the CTFG guidance became applicable and the MHRA GCP Inspectors continue to see non-compliance in this area. As described in a new post on the MHRA Inspectorate Blog (link here), the GCP inspectors have raised Critical Findings related to this topic for 8 organisations since 01-Jan-2019.

The MHRA Blog Post provides a list of common findings the inspectors continue to observe and includes recommendations to improve compliance. I encourage everyone to read the MHRA piece but I would like to highlight the following points:

• Reminder: The MHRA must approve the RSI and any changes via a substantial amendment. There must be a good rationale to include a SAR in the RSI, and appropriate risk mitigation measures should be in place.
• Onset date: The assessment of SARs expectedness should be based on the RSI valid at the time of occurrence, including for follow-up information, as opposed to Case Receipt Date.
• Comparator IMPs: the comparator SmPC should be reviewed periodically to evaluate the need for protocol amendment and/or re-consent.
• Fatal and Life-Threatening SARs: Although there might be exceptions, this type of events should not be considered expected. Auto-labelling systems may fail to consider event severity, which would then result in unreported SUSARs.
• RSI implementation date: The RSI must be approved at a trial level. Furthermore, in a trial conducted in both the UK and the EU, it must be approved by both the MHRA and all concerned EU authorities. As a tip, the MHRA considers that it can be useful to have trial-specific RSIs.
• RSI for a licensed product: It is generally not acceptable to copy and paste section 4.8 of the SmPC into the RSI section of an IB.
• Lack of Efficacy and Disease Progression: SARs due to lack of efficacy or disease progression should not be considered expected, unless this has been approved as part of the protocol and/or in the RSI.
• MedDRA terms and updates: A process must be in place to assess whether MedDRA updates have an impact on the RSI.

Photo by Sebastian Herrmann on Unsplash

In connection with this Blog Post, the MHRA has also published a new GCP Inspections metrics report, which covers inspections conducted from April 2018 to March 2019: link here

The report provides details about the 7 Critical Findings identified during inspections of Commercial Sponsors, which includes 2 Findings over Pharmacovigilance deficiencies: Critical Findings N°1 and N°5 both relate to deficiencies in the management of Reference Safety Information (RSI), which led to non-compliance with SUSAR and DSUR reporting requirements.

Based on the information presented in the Blog Post, we can expect to see more RSI Findings in the next GCP Inspections metrics report. So... Watch this space !!

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Thierry Hamard is a Pharmacist with more than 15 years of Global Pharmacovigilance Auditing experience and over 200 PV Audits performed since his company PV Focus was established in 2004.

Thierry is also Chief Editor of Safety Observer, a provider of Regulatory Intelligence services for Pharmacovigilance since 2005.

COVID-19 Guidance: Impact for Pharmacovigilance

LAST UPDATED 07-Oct-2021:

Where applicable, changes on this page and in the downloadable report are highlighted in Green.

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We are happy to share with you the result of our Regulatory Intelligence Monitoring regarding the guidance issued to address the COVID-19 pandemic.

We are highlighting the impact on Safety Reporting procedures for both Clinical Trial and Post-Marketing Pharmacovigilance activities. This information will be updated as necessary.

DISCLAIMER: This is not intended to cover all countries worldwide. For more information about the scope of our Regulatory Monitoring, please check our Q&As.

High Level Summary Clinical Trials: Most of the guidance documents that have been published are related to the conduct of Clinical Trials, and they are intended to protect subject safety and data validity. The impact for Pharmacovigilance groups in the Industry is limited as compliance with existing safety reporting requirements is generally expected. The European Commission held a webinar on 15-May-2020 to provide an overview of the most important elements of its Guidance on the management of clinical trials during the COVID-19 pandemic. Slides and Video Recording are made available. A few National Competent Authorities (e.g. France, the UK) have however published guidance to express their understanding that safety reporting timelines may not always be met, and that SUSARs submissions should have priority over periodic safety reports. Both the EMA and FDA have published guidance to help with the statistical analysis of trials impacted by COVID-19. The FDA has also issued a new guidance document to help assess the benefits of potential treatments on COVID-19-related symptoms during clinical trials. Multiple authorities around the world have also issued Guidance designed to fast-track the approval of modified vaccines targeting COVID-19 virus variants. Post-Marketing: At the European Level, the EMA has published guidance that describes how companies can prioritise ICSR Reporting activities. This guidance has been updated to cover Pharmacovigilance Quality Management aspects including CAPAs, Audits and Inspections. The European EFPIA issued additional guidance for the prioritization of Pharmacovigilance activities to mitigate the possible significant and sudden impact of COVID-19 on resources. The EMA has issued detailed guidance that provides recommendations for the processing and coding of ICSRs associated with products used for the treatment or prevention of COVID-19. The latter guidance has been revised reflect the update of MedDRA 23.0, which contains additional COVID-19- terms, which was implemented in EudraVigilance. The EMA also extended the Medical Literature Monitoring (MLM) service to include potential COVID-19 treatments. The MHRA has defined regulatory flexibility for certain Pharmacovigilance requirements including PSUR Submission, Safety Variations, dissemination of educational materials and DHPCs. ICSRs follow-up activities should also be prioritised to minimise the burden on Health Care Professionals. The MHRA has introduced an additional category to those defined at the EU level for the prioritization of ICSR submissions. The MHRA has also defined an urgent review procedure for the Relaxation of Risk Minimisation Measures. The FDA and Health Canada have published guidance that provides a framework to delay the submission of some reports, including ICSRs for non-priority products. The FDA has issued an updated version of its guidance on 11-May-2020, which brought important changes for the prioritization of 15-day Alert reports that should be submitted to the FDA. The FDA has also expressed their understanding that some REMS requirements may not be met during the Public Health Emergency. Following positive announcements on the efficacy of some COVID-19 vaccine candidates, the EMA has published new guidance to address specific considerations for Risk Management activities. This includes new guidance on Risk Management Plans (RMPs) for COVID-19 vaccines, which complements existing GVP Guidelines and brings a new safety reporting obligation for MAHs of COVID-19 vaccines. The EMA has published new guidance to address specific considerations for Periodic Safety Update Reports (PSURs), highlighting that the “Summary Monthly Safety Reports” required in EMA’s Core RMP Guidance document are not meant to replace the PSURs. The WHO has issued a new COVID-19 vaccine safety surveillance manual, which is intended to harmonise vaccine safety surveillance systems and vaccine safety communication during the COVID-19 pandemic. An additional module has now been published, which covers the safety surveillance of COVID-19 vaccines in pregnant and breastfeeding women. In line with their defined strategies, the EMA, the MHRA and the ANSM are all providing frequent updates about the safety of approved COVID-19 Vaccines. Authorities have concluded to a possible link between very rare cases of thromboembolic events with both the AstraZeneca and Janssen COVID-19 vaccines. More recently, these two vaccines have been linked to the occurrence of capillary leak syndrome whereas a risk of myocarditis and pericarditis has been associated with mRNA Vaccines (Pfizer/BioNTech and Moderna). Both the FDA and the EMA have warned about the risk of Guillain-Barré syndrome with Janssen’s Vaccine.

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Thierry Hamard is a Pharmacist with more than 15 years of Global Pharmacovigilance Auditing experience and over 200 PV Audits performed since his company PV Focus was established in 2004.

Thierry is also Chief Editor of Safety Observer, a provider of Regulatory Intelligence services for Pharmacovigilance since 2005.

Algeria issues New GVP Guideline

Things are changing fast in Algeria: It has only been a few months since a Note was published to describe revised Safety Reporting requirements (see Post) and the Algerian Authorities have now published a full Pharmacovigilance Guide with new changes to expedited reporting requirements.

The new Guide was produced by the "Centre National de Pharmacovigilance et de Materiovigilance" (CNPM) and includes a description of the local Pharmacovigilance System in Algeria. It covers the role of the stakeholders and includes a description of the obligations applicable to the Pharma Industry.

Among other topics, the Guide describes the expectations regarding the appointment of a Local Contact Person for Pharmacovigilance and for the maintenance and provision of the Pharmacovigilance System Master File (PSMF). The topics covered also include Procedures, Audits and Inspections, RMPs and PBRERs/PSURs, as well as Signal Management.

Regarding the Safety Reporting requirements, the Note published in June 2019 (see Post) reduced drastically the number of ICSRs that required submission in Algeria by removing the obligation to include foreign ICSRs. The new Guide brings yet more changes when compared to the June 2019 Note and here is a summary of the resulting applicable ICSR reporting requirements:

- Post-Marketing ICSRs, including cases originating from Non-Interventional Studies, must be submitted to the CNPM as follows:

• Domestic Serious ADRs: within 15 Calendar Days

• Domestic Non-Serious ADRs: within 90 Calendar Days

• All Foreign ADRs: through the PBRERs/PSURs

- Clinical Trials ICSRs must be submitted to the CNPM and Ethics Committees as follows:

• Domestic Fatal/Life-Threatening SARs: initial report within 7 Calendar Days

• Other Domestic SARs: within 15 Calendar Days

• All Foreign ICSRs: through Annual DSURs

In other words, compared to the Note published in June 2019, there is no longer a requirement to submit Domestic Fatal/Life-Threatening Post-Marketing ADRs in 7 Days.
On the other hand, the requirements for Clinical Trials ICSRs now includes all SARs, whether they are unexpected (i.e. SUSARs) or not.

The Guide produced by the CNPM is only available in French and is unfortunately not available on the website of the Agency. The copy shared here was obtained from a contact in Algeria and user of this blog, whom I would like to thank for notifying me of this new and important guidance.

   → Link to CNPM 2019 Pharmacovigilance Guide (in French)

   → Link to the CNPM website

   → For reference: Link to CNPM Note dated 03-Jun-2019 (in French)

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Thierry Hamard is a Pharmacist with more than 15 years of Global Pharmacovigilance Auditing experience and over 200 PV Audits performed since his company PV Focus was established in 2004.

Thierry is also Chief Editor of Safety Observer, a provider of Regulatory Intelligence services for Pharmacovigilance since 2005.

Algeria updates Pharmacovigilance reporting requirements

ATTENTION !! UPDATE 09-Jan-2020:
This post is no longer current as the CNPM has published a new Pharmacovigilance Guide with revised ICSR reporting requirements (see New Post). The content of this post includes the resulting revisions (in Red & Highlighted in Yellow).


The Algerian Authorities have published an important revision of the Note describing the Pharmacovigilance reporting requirements in the country.

Until now, the "Centre National de Pharmacovigilance et de Materiovigilance" (CNPM) required that all Serious ICSRs and Clinical Trial SUSARs be submitted, including foreign reports. This meant that thousands of ICSRs qualified for reporting to the CNPM in Algeria, even though it is doubtful that the CNPM had sufficient resources to process such large volumes of information.

The Note published by the CNPM and dated 03-Jun-2019 will come as a relief to international companies placing medicinal products on the market in Algeria: The expedited reporting of foreign ICSRs is no longer a requirement and those cases are now only expected to be presented through the applicable periodic reports.

As a summary in English, here are the newly applicable requirements in Algeria:

- Post-Marketing ADRs, including cases originating from Non-Interventional Studies, must be submitted to the CNPM as follows:

• Domestic Fatal/Life-Threatening ADRs: as soon as possible, within 7 Calendar Days
• Other Domestic Serious ADRs: within 15 Calendar Days
• Domestic Non-Serious ADRs: within 90 Calendar Days
• All Foreign ADRs: through the PBRERs/PSURs

The Note also now clearly states that the submission of PBRERs/PSURs can be aligned with the EURD List.


- Clinical Trials SUSARs must be submitted to the CNPM and Ethics Committees as follows:

• Domestic Fatal/Life-Threatening SUSARs: initial report within 7 Calendar Days
• Other Domestic SUSARs: within 15 Calendar Days
• All Foreign SUSARs: through 6-monthly Line Listings and Annual DSURs

As described in a recent article in the "Drug Safety" journal, the Algerian CNPM has not adopted the GVP Guideline for Arab countries published in 2014. With a 7-Day reporting requirement for Fatal/Life-Threatening ADRs, these new Requirements still deviate from the Arab GVPs and the underlying ICH E2D Guideline. Nevertheless, this revision represents a significant move towards international harmonization and will make compliance easier to achieve for the Industry in Algeria.

The Note issued by the CNPM is only available in French and is unfortunately not available on the website of the Agency. We obtained a copy from the CNPM, which we make available here, together with the previous version as a reference.

   → Link to CNPM Note dated 03-Jun-2019 (in French)

   → Link to the CNPM website

   → For reference: Link to CNPM Note dated 20-Oct-2017 (in French)

   → Link to Drug Safety article: “Pharmacovigilance Systems in Arab Countries”

   → Link to Guideline on GVP for Arab Countries (Version 2 – December 2014)

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Thierry Hamard is a Pharmacist with more than 15 years of Global Pharmacovigilance Auditing experience and over 200 PV Audits performed since his company PV Focus was established in 2004.

Thierry is also Chief Editor of Safety Observer, a provider of Regulatory Intelligence services for Pharmacovigilance since 2005.

RSI in Clinical Trials: EU Authorities set Compliance Date

As reported in the December 2017 issue of Safety Observer, the Heads of Medicines Agencies (HMA) have published a new version of their guidance document entitled “Questions and Answers – Reference Safety Information (RSI)”.

The new Q&As document explains what information the RSI should include and how it should be presented. Most importantly, it explains how it should be used in the context of applicable expedited (i.e. SUSAR) and periodic (i.e. DSUR) reporting.

If you have not read our blog post from January 2018 on this topic, you should really take the time and get to know the key messages brought by the new guidance: link here

EU Heads of Agencies set compliance date

The CTFG has now published a Cover Note where it acknowledges that the changes brought by the revised Q&As are significant. Although the document should be considered as applicable from the publication date, the Cover Note refers to a 1-year transition period until National Competent Authorities enforce the new requirements more strictly from 01-Jan-2019. The MHRA has also updated the guidance on its website accordingly.

Until then, Clinical Trial Applications and/or Substantial Amendment dossiers will not be rejected if the RSI is not completely in line the new Q&As, provided that the IB contains a RSI section that is considered fit for purpose. However the authorities may raise comments on the RSI and the sponsor will be expected to update the IB accordingly at the next routine update.

→ Direct link to CTFG Cover Note

→ Link to MHRA Clinical trial Guidance

Thierry Hamard (LinkedIn Profile) is a Pharmacist with more than 15 years of Global Pharmacovigilance Auditing experience and over 200 PV Audits performed since his company PV Focus was established in 2004.

Thierry is also Chief Editor of Safety Observer, a provider of Regulatory Intelligence services for Pharmacovigilance since 2005.

Reference Safety Information in Clinical Trials: The New EU Guidance explained

As reported in the December 2017 issue of Safety Observer, the Heads of Medicines Agencies (HMA) have published a new version of their guidance document entitled "Questions and Answers – Reference Safety Information (RSI)". This is a deliverable of the Clinical Trials Facilitation Group (CTFG), replacing the previous version dated December 2013.

The regulatory context and resulting issues

Until now, the relevant EU regulatory requirements were specified in the EU-CT 3 guideline published in June 2011 (link here) and the above mentioned CTFG Q&As introduced in December 2013 (link here).

Without going into too much detail, there were some gaps in this guidance and a number of companies received inspection findings for not meeting expectations in relation to the RSI, particularly in the context of SUSAR reporting.

As I have seen myself during audits, some companies merely included in their Investigator’s Brochure a list of all suspected ADRs observed during clinical trials, which they considered as the RSI. Needless to say that this did not help the clinical Investigator sites very much in getting familiar with the safety profile of the Investigational Medicinal Product (IMP).

Any new occurrence of an observed ADR was subsequently considered “expected” and no longer qualified for SUSAR reporting. Through this approach, the information necessary to monitor the safety profile of the IMP is only available to the Sponsor whereas the other stakeholders, including Authorities and Ethics Committees, are left in the dark, unable to fulfill their responsibilities with regards to subject protection.

Another aspect of the problem relates to the implementation of an updated RSI: As clearly specified in the existing guidance, a revised RSI should be submitted as a Substantial Amendment. What was not so clearly specified is that companies should not implement the updated RSI for expectedness assessment until it is approved by the Authorities.

As mentioned already, this has caused a number of Inspection Findings and companies have also seen some of their RSI Amendments rejected by the Authorities, in particular the MHRA.

The MHRA Inspectorate communicated about the issue, in an attempt to educate the Industry about their expectations:

• A first Blog Post was published in March 2016: Link Here
• The issue was subsequently discussed with Industry representatives at the MHRA GCP Stakeholder Engagement Meeting (StEM) on 18-Mar-2016 : Minutes and Presentations on this Page
• This was presented at the MHRA GCP Symposium in September 2016: Link Here
• A second Blog Post was published in January 2017: Link Here

As described in the EFPIA Position Paper published in September 2016 (Link Here), the industry expressed some concerns with the implications of this issue and called for better guidance, which has now led to the publication of the updated Q&As document.

The New RSI Q&As and the Key Take-Home Messages

One could challenge why this is not part of Eudralex Volume 10 but the important point is that new guidance is now available on the HMA website. The Q&As document has been expanded from 6 to 18 questions and from 3 to 19 pages to explain what information the RSI should include and how it should be presented. It includes clarifications on a number of rather technical aspects including the use of MedDRA terms, or the expression of frequency and severity of the events listed in the RSI. Moreover, it explains how it should be used in the context of applicable expedited (i.e. SUSAR) and periodic (i.e. DSUR) reporting.

Here is a list of the main requirements described in the new Q&As document (Link Here):

• Question 1: The content of the RSI should include a clear list of "expected" Serious Adverse Reactions (SARs) for the IMP, based on thorough causality assessment of observed SARs. This is therefore a subset of all observed SARs for which the Sponsor can justify a very strong plausibility of a causal relationship and it would generally exclude SARs that have been observed only once.
• Question 11: A Substantial Amendment is always required to be submitted if there are changes to the RSI.
• Question 12: This Substantial Amendment should be submitted to the authorities in all EU Member States where trials are ongoing in parallel to the DSUR submission.
• Question 12: The updated RSI can only be used for assessment of expectedness of SARs after the approval of the Substantial Amendment in all Member States where trials are ongoing.
• Question 12: The identification of SUSARs in the "Cumulative summary tabulation of serious adverse reactions" in a DSUR should be based on the version of the RSI most recently approved in all Member States (Note that this may not be the version "in effect at the start of the reporting period" as specified in CT-3)
• Question 17: When the WHO classification categories are used for causality assessment, "unlikely" is considered "not related".
• Question 18: The RSI used for the assessment of the initial SAR should be used to assess expectedness for follow up reports. SUSARs should not be downgraded even if the SAR became "expected" through an update of the RSI.

Where does this leave us ?

There is no doubt that the new guidance brings welcome clarifications on many aspects and the regulatory expectations are now clearly set for future inspections. It will also help many companies who did not know what information to include in the RSI or how to present it.

On the other hand, one of the concerns raised by the EFPIA was that companies consider the RSI as a global document. In order to comply with the new version of the Q&As and the requirement to make the RSI effective only after approval by all concerned EU member states, companies may need to use a different version of the RSI in Europe compared to other regions. Unfortunately we may not obtain the desirable harmonisation until the issue is discussed at ICH level.

Even within Europe, I know companies who are concerned by the potential delay it takes some authorities to approve Substantial Amendments, which I have heard can take up to 6 months even though the current guidelines specify a 35-Day response period…

In this context, some companies have decided to use a “tell, wait and do” procedure, which is used by the EMA for some variations to a Marketing Authorisation: In the cover letter, the Sponsor informs the receiving authority that unless stated otherwise, the RSI will be considered effective after a period of 60 days. Does this sound like a reasonable compromise ?

Please feel free to use the comment field at the bottom of this post to share your experience or concerns, or to explain what the new guidance will change for your company. Thank you !

Thierry Hamard (LinkedIn Profile) is a Pharmacist with more than 12 years of Global Pharmacovigilance Auditing experience and over 200 PV Audits performed since his company PV Focus was established in 2004.

Thierry is also Chief Editor of Safety Observer, a provider of Regulatory Intelligence services for Pharmacovigilance since 2005.