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.

It’s already Christmas !!

As we are nearing the festive season in our part of the world, I wanted to make a small present to my colleagues in the Pharmacovigilance community…

I agree that this is not a very sexy present. Not something that you put on your wish list or that you would enjoy with your friends or family: I am only offering you a free peek into the latest issue of Safety Observer, the leading Regulatory Monitoring Solution for Pharmacovigilance Professionals.

You can consult other free samples on the website but I am very aware that the value of the contents of each issue wears off with time. This is why I am offering you access to the full December issue for free !

Just click the picture to download your free copy and feel free to share with your contacts:

This issue was distributed to subscribers today: Thursday 07-Dec-2017. I hope you enjoy it and I would be delighted if this fresh issue can convince you of the value the service can bring to your organisation in the frame of your Regulatory Intelligence activities.

Please visit the website or contact me if you would like to know more about the service. Please also subscribe to the Free Monthly Updates and you will receive a discount code to be used against your first purchase through the website.

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.

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.