A new beginning...

It has been more than 7 years since the first website of Safety Observer was launched and it was time for an upgrade. The new website brings a modern look and corrects the issues we had with the former platform.

It includes a "News" section where we will publish free content on a regular basis. This comes in replacement of the blog published on this Blogger platform, which will no longer be maintained.

Please visit the "News" section of the Safety Observer website to access our future articles. The relevant content has also been migrated from this blog to the new website. You are invited to sign up for alerts in order to be notified of the publication of new articles and Regulatory Intelligence Reports.

We hope this nice tool will help us gain additional subscribers to our services and grow our customer base, which includes more than 100 companies to date !

Photo by Matt Botsford on Unsplash

------     THE END     ------

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 !!

_______________________________________

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

_______________________________________

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.

_______________________________________

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.

_______________________________________

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.

FDA Guidance on AE Reporting during a Pandemic

ATTENTION !!
This post was updated on 20-May-2020 to reflect the changes brought by the revised version of the Guidance Document published by the FDA on 11-May-2020. Resulting revisions are tracked (in Red & Highlighted in Yellow).



The U.S. FDA has published a new Guidance Document on 19-Mar-2020, which is entitled : “Postmarketing Adverse Event Reporting for Medical Products and Dietary Supplements During a Pandemic”.

This is not exactly a new document and in reality, this represents a minor revision of the 2012 guidance on “Postmarketing Adverse Event Reporting for Medical Products and Dietary Supplements During an Influenza Pandemic". The update clarifies that the guidance is applicable to any pandemic, including the current COVID-19 pandemic and not just an influenza pandemic.

Possible Impact of a Pandemic

This guidance provides recommendations to address the anticipated workforce shortage that can result from high absenteeism in the Industry and at the FDA during a pandemic, while the volume of case reports may increase due to the widespread use of medical products to face the pandemic.

Although compliance should be maintained to the maximum extent possible, the guidance brings flexibility to prioritize AE reporting responsibilities when resources become insufficient, which should be considered in Business Continuity arrangements.

Business Continuity and Prioritization

Companies that are unable to fulfill normal adverse event reporting requirements during a pandemic should maintain documentation of the declaration of a pandemic (e.g. by the WHO), and of the factors that are preventing the firm to comply with its reporting requirements, i.e. high absenteeism and/or increase in caseload. The FDA should be notified as soon as possible.

In these circumstances, the FDA will accept that certain safety reports are not submitted within the regulatory timeframes provided that delayed reports are submitted within 6 months of the restoration of AE reporting capabilities to their pre-pandemic state. However, a different timeframe may be set by the FDA (see Section D of the Guidance Document).

FDA defines Priorities for Safety Reports

The guidance includes a table that defines which reports companies should submit and which may be stored if necessary. Here is a summary for approved drug and biological products (NDA, ANDA, or BLA):

• FDA will communicate with firms if there are products and issues that present special concerns, in which case full compliance with expedited and periodic reporting requirements is expected.
• For all other products, Periodic Safety Reporting may be suspended.
• Regarding Expedited Safety Reporting (i.e. 15-day Alert reports), while other reports may be stored if necessary, the following reports should be submitted within required timeframes:

1-	Reports associated to products approved for an indication related to the pathogen causing the pandemic, including pandemic vaccines targeting the pathogen or the disease, whether or not this use is included in the approved labeling
2-	Reports associated to products approved within prior three years
3-	For Biologics only All Products, Reports with a Fatal Outcome

Besides these rules for approved drug and biological products, the table provides guidance for other types of products, including Prescription drug products marketed without an approved NDA (including compounded or repackaged products), Medical Devices, Blood Products, Human Cells, Tissue, and Cellular and Tissue-Based Products (HCT/P), etc.

→       Link to FDA Guidance Page

→       Direct link to FDA Guidance Document

_______________________________________

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.