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.

EMA Risk Management approach for COVID-19 vaccines

Further to the recent good news regarding the efficacy of COVID-19 vaccine candidates, European Authorities have published new guidance documents to support Risk Management activities for these vaccines once they are authorised.

    ⇒    Link to EMA News Release

Photo by Daniel Schludi on Unsplash

CoreRMP19 requirements and guidance

This includes a new guidance document published by the EMA to help companies prepare the Risk Management Plan (RMP) for their COVID-19 vaccines, which complements the existing GVP Guidelines and the associated RMP template. This document covers specific considerations for COVID-19 vaccines, including:

• The submission by MAHs of Summary Monthly Safety Reports to the EMA, to complement PSURs. As detailed within the guidance, these reports should include interval and cumulative summary tabulations of ADR reports, exposure data, ongoing and closed signals, etc.
• The need to adapt signal detection methods and practices to the expected large volume of ADR reports in the context of vaccination campaigns during a pandemic
• The need to consider global efforts to define the list of Adverse Events of Special Interest (AESIs)
• The need to consider the use of specific Follow-up Questionnaires for reports of identified safety concerns and suspected AESIs, while the burden on healthcare professionals should remain limited
• The need to consider missing information for specific populations, including pregnant women, patients with co-morbidities, elderly and children

   ⇒    Direct link to Core RMP guidance for COVID-19 vaccines

Please Note that a revision of the above guidance was published on 15-Jun-2021.

Photo by CDC on Unsplash

Pharmacovigilance Plan of the EU Regulatory Network

European Authorities have also produced a Safety Monitoring Plan for COVID-19 vaccines, which outlines how they intend to collect and review all relevant information once COVID-19 vaccines get authorised.

In addition to the EU GVPs, several activities will apply specifically to COVID-19 vaccines. As described above, this includes new reporting obligations for companies, who will be required to submit Summary Monthly Safety Reports to the EMA.

Transparency is an important theme of the plan, and it details the exceptional measures set up by the EMA to support public confidence and promote the uptake of COVID-19 vaccines. As an example, the EMA will publish on its website the full body of the RMP for all authorised COVID-19 vaccines, including Annex 4 presenting specific ADR follow-up forms.

    ⇒    Direct link to Pharmacovigilance Plan of the EU Regulatory Network

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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.

Interpersonal skills during audits and inspections…

Until now, I have used this blog to report on changes in the requirements applicable to Pharmacovigilance. This time is different and I would like to share the learning I took from a project I am involved with.

The story starts in the summer of 2017 when I received a call from a contact in the Global Pharmacovigilance group at Bayer. This contact knew me as a Pharmacovigilance Auditor and asked whether I would be interested to work on a coaching module. This module was part of a training programme the company was putting together to make people better prepared for Pharmacovigilance Audits and Inspections.

The Coaching Concept

One of the requirements was that I partner with another consultant that Bayer had identified for the project: A stage actress also working as a personal coach… How interesting !!

This is how I met Karin Seven, who has been working with professionals in the pharmaceutical industry for more than 20 years, helping them increase the impact of the messages they want to deliver during the course of their professional life.

Based on the requirements and objectives set by Bayer, we developed a concept for a full-day of individualised training following a standard agenda:

• During a baseline Mock Interview, I would cover topics relevant to each student in the same manner as I would do during a real audit, while Karin observed.
• Following an assessment review, we would then collectively discuss the strengths and weaknesses of the student, from both the content and behavioral perspective.
• Based on the assessment, Karin would work with the student through various exercises tailored to the individual’s needs, while I would review the documents requested during the Mock Interview. The exercises proposed by Karin are intended to help correct a range of personal habits that can include posture, breathing and voice coaching.
• I would then lead a second Mock Interview, providing the student the opportunity to put the lessons learnt into practice.

Examples of behavior to avoid…

Before I provide my feedback on this experience, I thought I would share a few examples of behaviors we sometimes see during audits and inspections, and which I DO NOT recommend:

• Appear disinterested and avoid eye contact
• Overuse filler words, e.g. “Humm” every two words
• Make an effort to refute any opportunity to cooperate in the audit/inspection process
• Talk with an inaudible voice that can be covered by the noise of the air-conditioning system
• Respond to questions with answers as long as possible, with a monotone voice and as fast as possible so there is little chance for anyone to take accurate notes
• Start answering before the auditor/inspector finished his/her question
• Start the interview with a lengthy PowerPoint presentation to waste time
• Act in such a way that the auditor/inspector feels like a pupil being taught a lesson…

The benefits of our Coaching Module

I am most impressed with the changes I can sometimes measure between the initial and the second Mock Interview. It is true that a few of our students did not really need much help, as they were already visibly confident in their responses but for others, I was amazed to see how much progress they made as a result of the coaching session. Instead of looking shy or confused, they managed to make slight behavioral changes that made their message much more impactful. They became more interesting to listen to, more self-confident and more convincing.

From an auditor’s perspective, it is of course clear that it will not be sufficient to deliver your message in a pleasant way if the content does not meet the expectations. We are trained to rely on evidence to assess compliance and you will not be able to hide the reality of a poor Pharmacovigilance System just by providing responses in a confident and decisive manner. However, clear and articulate responses delivered with confidence and ownership can only make the interview process more efficient and interesting for all those involved.

My part was rather easy: I just helped students become more familiar with the type of questions they may face during actual Pharmacovigilance Audits and Inspections. In my view, the coaching provided by Karin helped many of the students deliver their message in a more convincing manner. Even though this may not improve dramatically the outcome of an audit or inspection, I am convinced that the changes I have witnessed with some people will have a great impact for them, not only in their professional but also in their personal life if they choose so.

What’s your take on this ?

Please feel free to use the comment field at the bottom of this post to share your experience or comments. I am particularly curious to hear from my colleagues, Auditors and Inspectors…

Many thanks in advance !

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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.

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Karin Seven is working as a Coach and Trainer for more then 22 years. She is a qualified actress, working on stage for more than 30 years as actress or director.

Her expertise covers performance skill including speech, body language, posture, mindsets and radiance.

She is also the author of the book PowerAct - Deliver your best Performance, which is published in German by Haufe.

Revised ABPI Guidance for PV in Market Research

As reported in Safety Observer N°150 of November 2018, the ABPI (Association of the British Pharmaceutical Industry) has worked with BHBIA (British Healthcare Business Intelligence Association) to produce a revised version of their guidance on collecting Adverse Events, Product Complaints and Special Situations Reports during Market Research Programmes (MRPs). This is Version 4 of this valuable guidance document, which was first issued in October 2009.

In addition to changes related to Personal Data Protection, the main change concerns the collection of contact details when information is collected directly from patients/consumers in order to enable the appropriate follow-up of Adverse Events by the MAH.

For those who are not familiar with this document, it includes a series of useful annexes including example wording for the contract with the Market Research Agencies, templates for Data Collection and Reconciliation Forms, as well as interview scripts covering a range of scenarios.

The information presented on the BHBIA website also includes the Microsoft Word templates for the Data Collection and Reconciliation Forms, as well as suggested wording for Market Research Materials and a series of “Quick Guides”.

→       Link to ABPI News Release

→       Direct link to BHBIA/ABPI Guidance on PV in MRPs

→       Link to BHBIA Page

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.