31. Safety Signal – Introduction

What is Signal?

A signal is essentially a hypothesis of a risk with a medicine with data and arguments that support it, derived from data from one or more of many possible sources. 

The evidence in a signal is not conclusive (is, in the technical sense, uncertain), and is only an early indication (preliminary), as it may change substantially over time as more data accumulates. 

The evaluation of safety signals should be a continuous process in pharmacovigilance and it is essential that Manufacturing Authorization Holders (MAH’s) have a well-defined process to capture, evaluate, communicate and take action on potential PV risks, as needed. 

Definition:

The definition of a signal as provided by the Council for International Organizations of Medical Sciences (CIOMS) 8 Working Group:

Information that arises from one or multiple sources (including observations and experiments), which suggests a new potentially causal association, or a new aspect of a known association, between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory action.

Sometimes a signal may provide additional or new information about adverse or beneficial effects of an intervention, or information about an already-known association of a medicine with an adverse drug effect, for example: on the range of severity of the effect or its outcome; postulating a mechanism; indicating an at-risk group; suggesting a dose range which might be more risky/perilous, a pharmaceutical group-effect or a lack of effect by a particular medicine.

Signal management:

Signal Management is a set of activities performed to determine whether, based on an examination of individual case safety reports (ICSRs), aggregated data from active surveillance systems or studies, scientific literature information or other data sources, there are new risks associated with an active substance or a medicinal product or whether known risks have changed, as well as any related recommendations, decisions, communications and tracking. 

Activities include:

• Signal detection
• Signal validation
• Signal prioritization
• Signal assessment
• Recommendation for action
• Exchange of information

Goals of Safety Signal in Pharmacovigilance:

• Ensure safe use of drugs
• Early identification of associations between compounds and adverse events
• Highlight disproportionate and increased reporting
• Highlight important and unexpected events
• Support scientific decision-making
• Enable creation of hypothesis

Data sources for signal: 

• Preclinical data (e.g. animal toxicology studies)
• Clinical trials, observational studies
• Spontaneous reports
• Patient support programs, registries
• Social media
• Literature
• Regulatory database

How does signals are reviewed?

• Medical events (important, special interest, designated, targeted)
• Drug class
• Event severity and outcome, e.g. fatal
• Population (paediatric, geriatric, elderly)
• Type of administration
• Time period
• Other, e.g. literature, batches, lots

Method to review signal:

• a) Manually review each reported case qualitatively
• b) Establish frequency overviews
• c)With growing data size, use of statistical methods to aid quantitative review
• d) Employ disproportionality data mining algorithms

EMA’s Module IX – Signal management

Signal Management Overview:

First, a signal must be evaluated to determine if it is a valid safety signal by examining the clinical relevance and the strength of evidence of the available information. Main areas to keep focus on are four aspects of an adverse event, and look for trends:

1. Case Data & Case Quality – Is the signal associated with a trend related to frequency, seasonality, temporal association, geographical location, source, etc. as compared to historical data, expectations based on product distribution or clinical data? Is the data of good quality or are most of the cases assessed as unclassifiable because the information provided is insufficient or contradictory?
2. Patient Data – Is the signal associated with a trend related to the patient’s age, sex, race, profession, lifestyle, concomitant medical conditions, or other relevant factors?
3. Product Data – Is the signal associated with a trend related to the product’s use (or misuse), lot/serial/batch, location of manufacture, labeling, distribution, or lifecycle stage? Another critical information to include at this point, is product distribution and use data – to put the volume of reports received that are associated with the signal into a meaningful perspective. Evaluate the reporting rates over time and by any trend that allows you to further refine your signal validation.
4. Event Data – Is the signal associated with a trend related to severity, frequency, time to onset, duration, progression, outcome of the event?

What to Do with a Validated Signal?

Once signal is identified that warrants further evaluation, classify this it as a new risk or previously reported but changed in severity or frequency. 

It is useful to have a repository for all identified, on-going, or closed signals easily accessible to the signal management team. This allows for quick and easy assessment and decision making regarding action and communication.

Do not discard refuted signal data. Maintaining this in a searchable document management system can be very helpful for responding to NCA’s inquires or in evaluating similar signals in the future. 

Time for Action

If you determine the signal is a significant safety risk, the next step is to recommend appropriate action and communication. In the same way that Quality deviations are managed, PV safety signals may require an immediate corrective action (i.e. Health Authority or Market notification, stop sale, additional studies, increased data collection, etc.) and preventative action(s). By having a process to efficiently work up signals in place, driven by a tool that makes it quick and easy to gather the information needed at each step, partnered with Regulatory, Quality, and Business Operations input, management of PV signals puts us in a strong position to mitigate risks.