Revised ABPI Guidance for PV in Market Research

As reported in Safety Observer N°150 of November 2018, the ABPI (Association of the British Pharmaceutical Industry) has worked with BHBIA (British Healthcare Business Intelligence Association) to produce a revised version of their guidance on collecting Adverse Events, Product Complaints and Special Situations Reports during Market Research Programmes (MRPs). This is Version 4 of this valuable guidance document, which was first issued in October 2009.

In addition to changes related to Personal Data Protection, the main change concerns the collection of contact details when information is collected directly from patients/consumers in order to enable the appropriate follow-up of Adverse Events by the MAH.

For those who are not familiar with this document, it includes a series of useful annexes including example wording for the contract with the Market Research Agencies, templates for Data Collection and Reconciliation Forms, as well as interview scripts covering a range of scenarios.

The information presented on the BHBIA website also includes the Microsoft Word templates for the Data Collection and Reconciliation Forms, as well as suggested wording for Market Research Materials and a series of “Quick Guides”.

→       Link to ABPI News Release

→       Direct link to BHBIA/ABPI Guidance on PV in MRPs

→       Link to BHBIA Page

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.

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.

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)

___________________________

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.

_______________________

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.

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.

Reference Safety Information in Clinical Trials: The New EU Guidance explained

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)". This is a deliverable of the Clinical Trials Facilitation Group (CTFG), replacing the previous version dated December 2013.

The regulatory context and resulting issues

Until now, the relevant EU regulatory requirements were specified in the EU-CT 3 guideline published in June 2011 (link here) and the above mentioned CTFG Q&As introduced in December 2013 (link here).

Without going into too much detail, there were some gaps in this guidance and a number of companies received inspection findings for not meeting expectations in relation to the RSI, particularly in the context of SUSAR reporting.

As I have seen myself during audits, some companies merely included in their Investigator’s Brochure a list of all suspected ADRs observed during clinical trials, which they considered as the RSI. Needless to say that this did not help the clinical Investigator sites very much in getting familiar with the safety profile of the Investigational Medicinal Product (IMP).

Any new occurrence of an observed ADR was subsequently considered “expected” and no longer qualified for SUSAR reporting. Through this approach, the information necessary to monitor the safety profile of the IMP is only available to the Sponsor whereas the other stakeholders, including Authorities and Ethics Committees, are left in the dark, unable to fulfill their responsibilities with regards to subject protection.

Another aspect of the problem relates to the implementation of an updated RSI: As clearly specified in the existing guidance, a revised RSI should be submitted as a Substantial Amendment. What was not so clearly specified is that companies should not implement the updated RSI for expectedness assessment until it is approved by the Authorities.

As mentioned already, this has caused a number of Inspection Findings and companies have also seen some of their RSI Amendments rejected by the Authorities, in particular the MHRA.

The MHRA Inspectorate communicated about the issue, in an attempt to educate the Industry about their expectations:

• A first Blog Post was published in March 2016: Link Here
• The issue was subsequently discussed with Industry representatives at the MHRA GCP Stakeholder Engagement Meeting (StEM) on 18-Mar-2016 : Minutes and Presentations on this Page
• This was presented at the MHRA GCP Symposium in September 2016: Link Here
• A second Blog Post was published in January 2017: Link Here

As described in the EFPIA Position Paper published in September 2016 (Link Here), the industry expressed some concerns with the implications of this issue and called for better guidance, which has now led to the publication of the updated Q&As document.

The New RSI Q&As and the Key Take-Home Messages

One could challenge why this is not part of Eudralex Volume 10 but the important point is that new guidance is now available on the HMA website. The Q&As document has been expanded from 6 to 18 questions and from 3 to 19 pages to explain what information the RSI should include and how it should be presented. It includes clarifications on a number of rather technical aspects including the use of MedDRA terms, or the expression of frequency and severity of the events listed in the RSI. Moreover, it explains how it should be used in the context of applicable expedited (i.e. SUSAR) and periodic (i.e. DSUR) reporting.

Here is a list of the main requirements described in the new Q&As document (Link Here):

• Question 1: The content of the RSI should include a clear list of "expected" Serious Adverse Reactions (SARs) for the IMP, based on thorough causality assessment of observed SARs. This is therefore a subset of all observed SARs for which the Sponsor can justify a very strong plausibility of a causal relationship and it would generally exclude SARs that have been observed only once.
• Question 11: A Substantial Amendment is always required to be submitted if there are changes to the RSI.
• Question 12: This Substantial Amendment should be submitted to the authorities in all EU Member States where trials are ongoing in parallel to the DSUR submission.
• Question 12: The updated RSI can only be used for assessment of expectedness of SARs after the approval of the Substantial Amendment in all Member States where trials are ongoing.
• Question 12: The identification of SUSARs in the "Cumulative summary tabulation of serious adverse reactions" in a DSUR should be based on the version of the RSI most recently approved in all Member States (Note that this may not be the version "in effect at the start of the reporting period" as specified in CT-3)
• Question 17: When the WHO classification categories are used for causality assessment, "unlikely" is considered "not related".
• Question 18: The RSI used for the assessment of the initial SAR should be used to assess expectedness for follow up reports. SUSARs should not be downgraded even if the SAR became "expected" through an update of the RSI.

Where does this leave us ?

There is no doubt that the new guidance brings welcome clarifications on many aspects and the regulatory expectations are now clearly set for future inspections. It will also help many companies who did not know what information to include in the RSI or how to present it.

On the other hand, one of the concerns raised by the EFPIA was that companies consider the RSI as a global document. In order to comply with the new version of the Q&As and the requirement to make the RSI effective only after approval by all concerned EU member states, companies may need to use a different version of the RSI in Europe compared to other regions. Unfortunately we may not obtain the desirable harmonisation until the issue is discussed at ICH level.

Even within Europe, I know companies who are concerned by the potential delay it takes some authorities to approve Substantial Amendments, which I have heard can take up to 6 months even though the current guidelines specify a 35-Day response period…

In this context, some companies have decided to use a “tell, wait and do” procedure, which is used by the EMA for some variations to a Marketing Authorisation: In the cover letter, the Sponsor informs the receiving authority that unless stated otherwise, the RSI will be considered effective after a period of 60 days. Does this sound like a reasonable compromise ?

Please feel free to use the comment field at the bottom of this post to share your experience or concerns, or to explain what the new guidance will change for your company. Thank you !

Thierry Hamard (LinkedIn Profile) 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.