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.

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.

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.

RSI in Clinical Trials: EU Authorities set Compliance Date

As reported in the December 2017 issue of Safety Observer, the Heads of Medicines Agencies (HMA) have published a new version of their guidance document entitled “Questions and Answers – Reference Safety Information (RSI)”.

The new Q&As document explains what information the RSI should include and how it should be presented. Most importantly, it explains how it should be used in the context of applicable expedited (i.e. SUSAR) and periodic (i.e. DSUR) reporting.

If you have not read our blog post from January 2018 on this topic, you should really take the time and get to know the key messages brought by the new guidance: link here

EU Heads of Agencies set compliance date

The CTFG has now published a Cover Note where it acknowledges that the changes brought by the revised Q&As are significant. Although the document should be considered as applicable from the publication date, the Cover Note refers to a 1-year transition period until National Competent Authorities enforce the new requirements more strictly from 01-Jan-2019. The MHRA has also updated the guidance on its website accordingly.

Until then, Clinical Trial Applications and/or Substantial Amendment dossiers will not be rejected if the RSI is not completely in line the new Q&As, provided that the IB contains a RSI section that is considered fit for purpose. However the authorities may raise comments on the RSI and the sponsor will be expected to update the IB accordingly at the next routine update.

→ Direct link to CTFG Cover Note

→ Link to MHRA Clinical trial Guidance

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.