Things you should know about Signal Prioritization in the EU Signal Management Process

In today’s article, the subject is relatively lesser-known step in the EU signal management process. Signal Prioritization is obscure but very important to understand at the same time. I call it obscure because you won’t find all of the information below in one place. I scoured through some 8 sources to come up with all this.

The article covers concepts and definitions of signal prioritization, what actual and thematic parameters to consider while prioritizing signals, objectives, what actually WHO and MHRA do (methodologies), how actual prioritized signals look like and impact analysis of signal prioritization.

I hope you find this article useful and informative. Lets dive right in!

What is Signal Prioritization?

• The process, continuously performed throughout signal management, which aims to identify those signals suggesting risks with a potential important patients’ or public health impact or which may significantly affect the risk-benefit balance of the medicinal product and thus require urgent attention and management without delay.

MAH performs signal prioritization to identify signals which may adversely impact:

1- Public health

2- Individual patients

3- BR balance of the product

• So things to remember about prioritization: Continuous, impact on public/patient health/BR balance and require urgent attention

Objectives of signal prioritization/ What MAHs should keep in mind:

1- Is the step that determines the timeline for signal assessment and recommendation of action

2- Issues derived from non-valid events that do not qualify as ICSRs

What MAH should keep in mind during signal prioritization:

Take a pause, see where you are NOW:

• Consider throughout process if the information available suggests that there could be a risk that requires prevention or minimization in a timely manner

2- Being prepared to take action before process completion:

• May need to implement these measures before a formal assessment of the signal is concluded and things become ‘official’.

3- Be human, use nuance and be ready:

• Always use clinical judgement and flexibility throughout the process.

Signal Prioritization should be based on (actual/clinical parameters):

1. Severity, seriousness, outcome and reversibility of the adverse reaction and the potential for prevention
2. Patient exposure and the estimated frequency of the adverse reaction.
3. Patient exposure in vulnerable populations and/or in populations with different patterns of use, where appropriate.
4. The consequences of treatment discontinuation on the disease under treatment and the availability of other therapeutic options.
5. The expected extent of the regulatory intervention (e.g. addition of adverse reactions, warnings, contraindications, additional risk minimization measures, suspension, revocation).
6. Whether the signal is likely to apply to other substances of the same class of medicinal products
7. Strength and consistency of the evidence supporting an association.
8. Signals that could cause media attention and/or public concerns.
9. Every organization should consider throughout the signal management process whether signals suggest risks with an important impact on patients’ or public health and/or on the risk-benefit balance of the medicinal product.

Signal prioritization: what points to consider (thematic):

1. Clinical Impact on patients:

• Impact on patients depending on the severity, reversibility, potential for prevention and clinical outcome of the association.

2. Consequences of treatment discontinuation:

• Consequences of treatment discontinuation on the disease and the availability of other therapeutic options

3. The evidence- strength and consistency:

• Strength and consistency of the evidence supporting the association as, for example, biological plausibility, a high number of cases reported in a short period of time, identification of the signal in different settings, data sources or countries.

4. Clinical (co-existence) context:

• Clinical context, that is, whether the association suggests a clinical syndrome that may include other reactions.

5. Public health impact:

• Public health impact, including the extent of utilization of the product in the general population and in special populations and the patterns of the medicinal product utilization.

6- Ongoing investigations with pending verdicts:

• If a marketing authorization application for a new medicinal product is still under evaluation
• Enter the outcome of the signal prioritization process in the product safety signal monitoring tracking sheet.

Signal Prioritization Methods:

Various organizations and MAHs have own methodologies.

In this article, two different regulatory methodologies for signal prioritization are discussed.

1- WHO Method of signal prioritization

2- MHRA Method of signal prioritization

1- WHO method of signal prioritization:

• In the WHO method of signal prioritization, following aspects of the signal are each evaluated and then an overall priority is placed on the signal that drives the formal evaluation of the finding:

1. Seriousness

2. Unexpectedness

3. Strength of disproportionality score

4. The temporal displacement of disproportionality score

5. Age of the product

6. Signaling in multiple countries

7. Positive re-challenge

8. Existence of the signal term on a list of targeted terms

2- MHRA Method of signal Prioritization:

MHRA uses signal triage method.

• They analyze the immediate and high-risk signal attributes first

• These aspects drive formal evaluation

• While lower signal attributes are postponed for formal evaluation until a later time

- All in all, this triage is done using final priority score to triage and prioritize and to decide further action

What happens after getting final priority score at MHRA?

• The combination of this score is used in an undisclosed manner to categorize the signal into a final category of High, more information required, Low, or No action.

How the MHRA Signal Prioritization method derives the final priority score?

• During signal prioritization process at MHRA, goal is to gain the final priority score.

This final priority score is made of two scores:

1. Evidence score

2. Public Health score

Evidence scores:

It is an algorithmic score based largely on:

1. The strength of the disproportionality metric value

2. Plausibility of causal relationship

3. Strength of the evidence provided

Public health score:

1. Number of cases per year

2. Anticipated health consequences

3. The reporting rate in relation to the level of drug exposure

What actual signal prioritization looks like with timelines:

Impact analysis for signal prioritization:

While analyzing impact of a signal during the process of prioritization, six points should be considered:

1. What type of event — serious/severe

2. Is it reversible

3. Is it preventable

4. Strength of association

5. Likely to be a contraindication or W&P

6. Exposure — vulnerable patient population

So that is this quick article on Signal Priortization in the EU signal management process! I hope you found this article informative.

Please share your thoughts the comments section below!

Further reading:

You have read the article on signal priortization. Now compare and contrast with emerging safety issues in my article below!

A 4-minutes synopsis on Emerging Safety Issues in EU signal management process | LinkedIn

Happy reading!!