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.

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

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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.

Established products to exit EU list of Black Triangle Products ?

As reported in Safety Observer N°148 of September 2018, the EMA has published the minutes of the 100th Management Board meeting, which took place on 06 and 07-Jun-2018.

The Board discussed a great variety of topics, including Brexit and lessons learnt after the first EMA Public Hearing. It also included a discussion on a report exploring the experience made with the list of products subject to additional monitoring, also known as the list of Black Triangle Products.

As described in GVP Module X, all medicines on the list must be identified with an inverted Black Triangle, which is displayed in their package leaflet and in the SmPC. This system was derived from the Black Triangle scheme already in place in the UK to highlight the medicines under close scrutiny by the authorities, which was expanded throughout Europe with the implementation of the 2010 Pharmacovigilance Legislation. The EMA published the list for the first time in April 2013 and it is reviewed every month by the PRAC.

There are a few reasons that can make a medicine enter the list, knowing that it should remain on the list for 5 years unless the PRAC decides otherwise:

• It contains a new active substance or a new biological/biosimilar product

• It has been given a conditional approval, or approved under exceptional circumstances or with specific obligations on the recording of suspected ADRs

• The company that markets the medicine is required to conduct a post-authorisation safety study (PASS)

One of the main conclusions of the report discussed by the Board is that the latter criterion has led to the inclusion of a large number of established products in the list (see item B.9 in the minutes). This is reportedly of limited value and the PRAC supports that this category of products should be removed from the scope of additional monitoring.

Based on the current list (i.e. Revision 58 dated 25-Jul-2018), there are 57 out of 346 active substances that are on the list only because of a required PASS. They are not all established products but those are easy to spot because the number of products and MAHs concerned is so large that they need to be presented in Annexes separate to the list. For example, the list of Domperidone-containing medicinal products (Annex X) is 6 pages long. Even though each formulation / MAH / Country is presented, it still concerns a large number of products indeed.

Based on the report and the opinion of the PRAC Committee, this may change in the future and these products would no longer qualify for the Black Triangle scheme in the EU. Following endorsement by the Heads of Medicines Agencies (HMA), the report will be sent to the European Commission for further consideration and decision by the European Parliament and Council.

→       Link to EMA Management Board Meeting Page

→       Direct link to EMA Management Board 100th Meeting Minutes

→       Link to EMA Page: Medicines under additional monitoring

→       Link to EMA Page: List of medicines under additional monitoring

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.

Medication Errors in France: Q&As now published !

The publication of the new version of the French Good Pharmacovigilance Practices in February 2018 brought some confusion regarding the obligation for Marketing Authorization Holders (MAHs) and "Exploitants" to submit specific reports to regulatory bodies outside of the EudraVigilance network.

As mentioned earlier (link to our June2018 post here), we questioned the French Agency about the apparent additional requirement to submit Reports of Medication Errors with no Adverse Reaction, as well as Reports of Abuse or Dependence to medicines containing psychoactive substances.

The response we received brought valuable information and announced the imminent release of a Questions & Answers Document to address the need for clarification. The wait was short and the ANSM has now published this Q&A Document, which provides additional information on the role and obligations of the MAH and "Exploitant".

In line with the response shared earlier, it confirms that there is no obligation for Pharma Companies to submit Medication Errors without adverse reactions to the dedicated ANSM Medication Error Desk. As already mentioned, all confirmed Medication Errors (with or without Adverse Reactions) must be assessed in the corresponding PSUR and taken into account in the evaluation of benefits and risks of Medicinal Products.

In the same way, the Q&A Document clarifies that there is no obligation for MAHs and "Exploitants" to submit reports of abuse or dependence to medicines containing psychoactive substances to the Dependence Evaluation and Information Center (CEIP).

These clarifications will be reflected in the French Good Pharmacovigilance Practices, which should be revised accordingly in the near future.

Please note that the Q&A Document also clarifies the expectations regarding additional aspects of the local Pharmacovigilance System including the responsibilities of the local contact person for Pharmacovigilance, local PSMF, local Signal Detection activities and Risk Management, etc.

➝ Link to ANSM Q&A on the French GVPs (in French)

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Raphaëlle KUHN is a Pharmacist with over 9 years of experience in the pharmacovigilance and clinical trial safety area. She has been working as a Pharmacovigilance Consultant within SUNNIKAN Consulting for 6 years where she supports clients in quality management activities and has conducted over 80 audits internationally.

Raphaëlle also contributes to the monthly Pharmacovigilance Regulatory Intelligence bulletin Safety Observer with regards to the French announcements.