A 5-minutes synopsis on Emerging Safety Issues in EU signal management process

Signal management process in the EU and worldwide is a fascinating PVG discipline which is full of contradictions!

It is perhaps the most demanding line in terms of scientific and evidence based thinking in all of the PVG branches (Aggregate, RMP and signal). It also remains the most automated PVG discipline as well, however, for all AI and automation tools in quantitative signal detection, human insights and medical reviewer expertise are absolutely vital in overall global signal governance. Humans, just are indesepensible in the process.

I intend to write more on various aspects of signal management process in the upcoming articles. Its’s a small start with a quick synospsis on emerging safety issues.

I have kept it short and to the point. It won't take more than 5 minutes of your time. I hope you like this article.

Emerging safety issues in EU signal management process: What are they?

• A safety issue considered by a marketing authorization holder to require urgent attention by the competent authority because of the potential major impact on the risk-benefit balance of the medicinal product and/or on patients’ or public health and the potential need for prompt regulatory action and communication to patients and healthcare professionals.
• Events may occur, which do not fall within the definition of reportable valid ICSRs, and thus are not subject to the reporting requirements, even though they may lead to changes in the known risk-benefit balance of a medicinal product and/or impact on public health.

Examples of ESIs:

1- Major safety findings from a newly completed non-clinical study

2- Major safety concerns identified in the course of a non-interventional post-authorization study or of a clinical trial

3- Safety issues published in the scientific and medical literature

4- Safety issues arising from the signal detection activities

5- Signals of a possible teratogenic effect

6- Safety issues related to the use within or outside the terms of the marketing authorisation

7- Safety issues due to misinformation in the product information

8- Marketing authorisation withdrawal, non-renewal, revocation or suspension outside the EU for safety-related reasons

9- Urgent safety restrictions outside the EU

10- Safety issues in relation to the supply of raw material

11- Lack of supply of medicines

Further Examples of ESIs include:

• Major safety issues identified in the context of ongoing or newly completed studies, e.g. an unexpectedly increased rate of fatal or life-threatening AEs
• Major safety issues identified through the spontaneous reporting system or publications in the scientific literature, which may lead to considering a contraindication, a restriction of use of a medicinal product or its withdrawal from the market (changes in RSI safety sections)
• Major safety-related regulatory actions outside the EU, e.g. a restriction of use of a medicinal product or its suspension.

Note: What are urgent safety restrictions?

• Urgent Safety Restriction (USR) is a regulatory action taken, in response to a safety signal, to make an interim change to the terms of the marketing authorization for a medicinal product in Europe
• MA change inspired by RA in response to a signal = Urgent Safety Restriction
• Whereas safety alert/alert is RA response to an identified risk

Reporting requirements about emerging safety issues:

• When the MAH becomes aware of an emerging safety issue from any, they should notify it in writing to the regulators.

Notification of ESI should include the following:

1.Description of the safety issue

2.The source(s) of information

3.Any planned or taken actions with timelines

4.Any relevant documentation available at the time of initial notification

• The MAH should collaborate with the regulators in the assessment of the emerging safety issue.

• In order to ensure its effectiveness, the system should not be saturated by the transmission of less urgent information.

• Caution:

MAHs should only communicate as emerging safety issues those safety concerns which meet the definition provided above whose urgency and seriousness cannot permit any delay in handling.

ESIs: MAH obligations

• Emerging Safety Issues should be communicated in writing to the competent authorities in Member States where the medicinal product is authorized and to the Agency via email within three working days.
• This should be done immediately when becoming aware of them.
• The document should indicate the points of concern and the actions proposed in relation to the marketing application/authorization for the concerned medicinal product.
• ESI should also be analyzed in the relevant sections of the periodic safety update report of the authorized medicinal product.
• Variation and or update to RMP–as a result of signal validation — as soon as possible and no later than 3 months after signal completing the assessment of the signal if it corresponds to an important risk (see GVP Annex I), or within 6 months for adverse reactions or risks not considered important.
• Use the PSUR (if PSUR to be submitted within 6 months of detection)
• Otherwise use standalone signal notification form on EMA website

Last word:

So, in short, MAH has to communicate as early as possible in 3 days, in writing to EU member states of authorized product and to EMA via email with points of concern and proposed actions, also should discuss in PSUR.

How MAH can communicate emerging safety issue with the EMA:

• So, once MAH has identified ESI and it has a significant impact on the benefit-risk balance of a product-

•MAH should notify in writing as an Emerging safety issue on the email address to EMA:

→ P-PV-emerging-safety-issue@ema.europa.eu

• MAH should communicate to the EU member states where they have MA
• As well as to the EMA

Quick recap: Take home summary: ESIs.

•These are issues identified by the client

• They are important because of the major impact they can inflict on:

1.The risk-benefit balance of the medicinal product

2.On patients’ or public health

• The MAH has to notify the regulators ASAP but within 3 days maximum of becoming aware of ESI in writing with

1.Points of concerns

2.Plan of action

• Regulators have to promptly communicate with general public/patients about these issues and take urgent action on them to prevent harm

So that was it for this article. I hope you liked it.

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