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.

EMA Guidance on ICSR data from EudraVigilance

Everybody should know by now but in case you missed it, the EMA published much-awaited guidance over the summer to clarify the obligations of MAHs to record information on ICSRs they can access in EudraVigilance.

Since the implementation of the New EudraVigilance on 22-Nov-2017, MAHs are given access to all ICSRs contained in the EudraVigilance database. The MAHs are now responsible to access EudraVigilance to retrieve all ICSRs related to their medicines and first received by National Authorities.

There was however no guidance regarding the obligations of MAHs in relation to ICSRs submitted to EudraVigilance by other MAHs or regarding those ICSRs available in EudraVigilance prior to 22-Nov-2017. This has caused a lot of pain and confusion, especially for MAHs of generic products who could not exclude ownership of the suspected products in many ICSRs they became aware of.

This gap has now been closed by the EMA and the Note for Clarification published on 23-Jul-2018 brings much needed guidance:

• Regarding the ICSRs available in EudraVigilance prior to 22-Nov-2017, the Note clarifies that MAHs have no obligation to screen EudraVigilance for cases that they do not already have in their own database. In the same way, the MAH have no obligation to record in their database those ICSRs they become aware through activities related to Signal Management in EudraVigilance.

• Regarding the ICSRs submitted by other MAHs to EudraVigilance, the Note clarifies that MAHs have no obligation to record these in their own database.

Although some will argue this took a long time and could have been better anticipated, this should come as a relief for the industry. It also sets a clear standard for Regulatory Inspections.

→ Link to EMA Page: Access to EudraVigilance data

→ Direct link to Note for Clarification

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

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

About the reporting of Medication Errors in France...

Although mostly in line with the European legislation, the new version of the French Good Pharmacovigilance Practices published in February 2018 introduced a few new requirements for Marketing Authorization Holders and "Exploitants". As specified in article 4.32, these new obligations include the submission of:

• Reports of Medication Errors with no Adverse Reaction to the dedicated ANSM Medication Error Desk,
• Reports of Abuse or Dependence to medicines containing psychoactive substances through the Dependence Evaluation and Information Center (CEIP-A).

Since the reporting of Medication Errors without Adverse Reactions was not required for Marketing Authorization Holders and "Exploitants" prior to February 2018 and no information on the modalities of reporting were provided (i.e. timelines and format), we contacted the French Agency to request some clarifications. We also asked confirmation regarding the duplicate submission of Reports of Abuse or Dependence to medicines containing psychoactive substances, as those cases are already required to be reported to EudraVigilance (see articles 4.13, 4.14 and 4.15 of the French GVPs).

We have just received a response from the Medication Error Desk, which clarifies that pharmaceutical companies do not have any obligation to report Medication Errors without Adverse Reactions to the ANSM Medication Error Desk. A Questions & Answers Document should be published by the Agency shortly, pending the correction of article 4.32 of the French GVPs. The response included a reminder that confirmed Medication Errors associated or not to an Adverse Reaction must be assessed in the PSUR, as specified in the EU GVP Module VI (see VI.B.6.3). Medication Errors and the risk of Medication Errors must also be taken into account in the framework of the monitoring of the safe use of medicines and the assessment of risks and benefits.

Below is a copy of the response we received from the ANSM Medication Error Desk (in French !):

"Nous vous remercions pour votre message. Nous tenions à vous préciser que les industriels n’ont pas d’obligation à déclarer les erreurs médicamenteuses sans effet indésirable au Guichet Erreurs Médicamenteuses de l’ANSM.

Une Foire aux questions sera prochainement publiée par l'agence dans l'attente d'un rectificatif de l’article 4.32 du chapitre 4 des BPPV.

Néanmoins, l’ensemble des erreurs médicamenteuses avérées ayant entraîné ou non un effet indésirable doivent être évaluées dans le rapport périodique de pharmacovigilance. Il est important que tout signalement d’erreur ou de risque d’erreur soit pris en compte dans le cadre du suivi de la sécurité d’emploi et de l’évaluation du rapport bénéfice/risque."

At this time, we have not received a response regarding reports of abuse or dependence cases, and we will update this blog when this information becomes available.

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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.

EMA Signal Detection Pilot and New MAs…

The Signal Detection Pilot started on 22-Feb-2018 and concerned MAHs are now required to monitor EudraVigilance data and inform Authorities of validated signals detected in the database. Only those MAHs whose active substances are included in the list of products involved in the pilot are subject to these new requirements.

In March 2018, we published the response we received from the EMA to a question we asked regarding the possible addition of New Active Substances to the list. We were wondering whether the new requirements would apply to companies who get a new substance approved while the pilot is ongoing but the EMA confirmed that the list of substances involved in the pilot is fixed and will not change (link to our March 2018 post here).

Anna Marques, EU QPPV at Eignapharma (link to their website here), was wondering about another scenario: What if you get a new Marketing Authorisation for a product that is already in the list, for instance if you register a new generic product ?

That’s also an interesting question and I would like to thank Anna for accepting to share the response she received from the EMA, which states that the new requirements do not apply to products that became authorised after the start of the pilot. Anna’s exchange with the EMA is available in a comment to our March 2018 post (link to our March 2018 post here).

In conclusion, only companies that were MAHs for products included in the list at the beginning of the pilot are concerned by the new Signal Detection requirements and this will not change during the pilot. I hope this helps !

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

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

EMA Signal Detection Pilot and New Active Substances…

As everyone knows, the New EudraVigilance System was implemented on 22-Nov-2017 and brings enhanced Signal Detection and Data Analysis tools to support safety monitoring directly by MAHs.

As described in the latest revision of GVP Module IX on Signal Management, Marketing Authorisation Holders (MAHs) have a requirement to continuously monitor EudraVigilance data and inform EMA and National Competent Authorities of validated signals detected in the database.

Transitional arrangements have however been agreed in order to streamline the implementation of this new process and during a pilot period of one year starting on 22-Feb-2018, only those MAHs whose active substances are included in the list of products involved in the pilot will be subject to the new requirements.

The list of substances involved in the pilot was first published by the EMA on 27-Oct-2017 and was last corrected on 14-Feb-2018 (Link to EMA Signal Management Page Here).

As initially communicated by the EMA, the list of substances involved in the pilot is based on the list of medicines under additional monitoring in the EU, i.e. the list of Black Triangle Products, which is revised on a monthly basis by the EMA (Link to EMA List of Medicines Under Additional Monitoring Here). And this made us wonder…

Can products be added to the list during the Pilot ?

I have worked for a Start-Up company recently which is awaiting its first Marketing Authorisation in Europe. As the product is a new active substance, it will obviously be added to the list of Black Triangle Products and so we were wondering whether the product will also be added to the list of substances involved in the Signal Detection pilot.

I tried to find the response to this question in the information available on the EMA website but I could not find what I was looking for. And so I sent my question to the EMA.

EMA Says No !

I was pleased to receive a conclusive response within a day, and the EMA confirmed that the list of substances involved in the pilot is fixed and will not change over the duration of the pilot.

I don’t know if many people also wondered about this but I hope this is helpful. I believe the EMA has since removed any reference to the list of Black Triangle Products for the avoidance of doubt.

Here is a copy of the exchange I had with the EMA:

I wonder if you could clarify this for me : I know that the list of products for the Signal Detection pilot is based on the list of products under additional monitoring. If a new product is approved over the next year, it will go to the list of Black Triangle products but what about the Signal Detection pilot ? Will the list of products for the pilot be revised on an on-going basis or is fixed for the year to come ? Many thanks in advance.

Re: EMA request reference ASK-39482

Dear Mr Hamard,

Thank you for your query.

We confirm that the pilot list is fixed i.e. it will not be affected by changes to the additional monitoring list (additions or deletions).

Best regards,

European Medicines Agency

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

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

Signal Detection with EudraVigilance: A brief overview of changes to come

This post provides a short overview of the upcoming changes in relation to Signal Detection in Europe and the resulting new obligations for Marketing Authorisation Holders.

EMA issues revised GVP Module IX on Signal Management (12-Oct-2017)

The EMA has now released the final version of GVP Module IX on Signal Management (Rev. 1), which includes guidance for the continuous monitoring of EudraVigilance data by Marketing Authorisation Holders (MAHs).

It specifies that EudraVigilance data should be reviewed with a frequency proportionate to the identified risk, at least every 6 months. Module IX also describes the procedural options available to MAHs in the event they identify validated signals.

Methodological aspects of signal detection are now addressed separately in a new Addendum I, which introduces the concept of Designated Medical Events (DMEs). The list of DMEs contains 62 MedDRA Preferred Terms corresponding to serious medical concepts often causally associated with drugs across multiple classes.

EMA provides information on Signal Detection Pilot (27-Oct-2017)

As described in GVP Module IX, MAHs have a requirement to continuously monitor EudraVigilance data and inform the EMA and EU National Competent Authorities of validated signals detected in the database. This will become possible with the implementation of the new EudraVigilance system on 22-Nov-2017.

The EMA has defined transitional arrangements to streamline the implementation of this new process. During a pilot period of one year, only MAHs whose active substances are included in the list of medicines under additional monitoring will be subject to the new requirements.

This will apply from 22-Feb-2018, allowing 3 months for MAHs to become familiar with the new EudraVigilance system and adapt their processes. Other MAHs will have access to EudraVigilance data but the new obligations will not apply to them until the pilot is completed and the EMA defines the next phase of implementation.

Explore the topic further: Free Webinar !

Essjay Solutions Ltd will hold a Free Webinar on Signal Detection and EudraVigilance, which will provide an overview of these changes and offer some advice on how to manage them. This webinar will take place on 21-Nov-2017 at 11:00 AM GMT.

→  Link to EMA GVP Page

→  Link to EMA Signal Management Page (includes DME List)

→  Link to Essjay Solutions Webinar Registration Page

Thierry Hamard 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.

EMA issues go-live plan for the new EudraVigilance

The implementation of the new EudraVigilance system requires the migration of more than 11 million cases from the current database, which will be completed from 08 to 21-Nov-2017 when some functionalities of the system will be unavailable. The electronic submissions of data on medicines (Article 57) will be unavailable whereas the electronic reporting of ICSRs by National Competent Authorities (NCAs), Marketing Authorisation Holders (MAHs) and Sponsors of Clinical Trials (Sponsors) will be disrupted.

The go-live plan published by the EMA describes the alternative reporting arrangements during the cutover period, and three options are presented separately for Clinical Trial SUSARs and Post-marketing ICSRs:

• Option 1: The submission is stopped. This applies to EudraVigilance but also to a list of NCAs, some of which will stop sending/receiving cases as early as 04-Nov-2017.
• Option 2: The MAH/Sponsor has to follow alternative arrangements (e.g. fax or email) for submission to NCAs during the cutover period.
• Option 3: No change to current arrangements. The MAH/Sponsor continues with the electronic submission of NCAs, which applies in the UK (MHRA) and Germany (BfArM and PEI). Specifically for SUSARs, Option 3 also applies to NCAs that do not currently accept E2B reports (e.g. France) and Sponsors should continue with the current reporting method (e.g. email or web portal).

Following the launch of the new EudraVigilance system on 22-Nov-2017, all reports that could not be submitted electronically during the cutover period will need to be submitted within 2 EMA business days following the go-live of EudraVigilance, i.e. by 24-Nov-2017.

Regarding Post-Marketing ICSRs routinely sent by NCAs to MAHs, the MAHs will need to use EVWEB functionalities to download the reports submitted by NCAs to EudraVigilance and the corresponding ICSRs will be available for download as of 23-Nov-2017.

The Medical literature monitoring (MLM) by the EMA will continue during the cutover period but the screening results will only become available to MAHs in the restricted area of EudraVigilance on 22-Nov-2017. The resulting valid cases will be entered from 20 to 30-Nov-2017 and the corresponding ICSRs will again start to become available for download by MAHs as of 23-Nov-2017.

In addition to the go-live plan, the EMA has published a short Technical Note that describes the impact of the planned downtime on other IT systems and provides corresponding instructions. This concerns for example submission to the PSUR Repository and EudraCT database.

→    Link to EMA News Release

→    Link to EudraVigilance Page

→    Direct link to EudraVigilance Go-Live Plan

→    Direct link to Technical Note

Thierry Hamard 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.