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

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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.

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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.

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.

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.

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.