To put in simple terms signal in pharmacovigilance (PV) is any new information that

• Suggests a new causal association or
• A new aspect of a known association

Signal can be either beneficial or adverse. Adverse signals, often called as safety signals are an important part of pharmacovigilance system.

Source of signals

Signals can arise from any source of data that a PV system encompasses of. The common sources of signals are:

• Spontaneous reporting systems – Individual case study report (ICSRs) that are databased
• Active surveillance systems – Sentinel sites, Registries
• Literature

Signal management process

As a Marketing authorization holder (MAH) of pharmaceutical products, companies hold the responsibility to have an organized signal management process within their PV systems.

It includes various processes starting from signal identification to its closure. They are:

1. Signal detection
2. Signal validation
3. Signal prioritization
4. Signal assessment
5. Recommendations for action

Signal detection

This involves the identification of signals through one or more of the below methods

• Traditional – Case and case series review – This involves review of spontaneous reports and other postmarketing adverse events (AEs). The ‘index case’ or a ‘sentinel case’ which strongly supports causality of an AE with the drug leads to the identification of signals
• Traditional – Analysis of larger datasets – Involves analysis of line listings, cumulative tables or periodic safety reports. Changes in frequency, distribution, duration, severity or outcome of AEs are looked into.
• Statistical methods – These methods are generally employed when the database to be analyzed is too large for inspection of individual cases. These methods focus on groups of cases to identify high proportions of specific AE compared to the reporting of this event for all other medicinal products (disproportionate reporting).
  • Disproportionate reporting – Ratio of proportion of ICSRs of a specific AE in the presence and absence of a specific drug. A high value of the ration in a particular Drug-Event combination (DEC) suggests further investigation.
• Methods aimed at specific groups of AEs – A best example of such groups is Designated Medical events (DMEs). Some AEs are known to be caused due to exposure to drug and draw attention of signal assessors.

Signal validation

Also known as signal evaluation, aims at determining whether sufficient evidence exists to identify a causal association in the detected signal. Signal validation is done based on

• Previous awareness – Information that is already knowns regarding the detected signal and which is included in the product information (summary of product characteristics (SmPC) and package leaflet) and information regarding any previous assessment of the association.
• Strength of evidence – Quality of the data and consistency of evidence across cases and various data sources.
• Clinical relevance – Seriousness and severity of AE, outcome and reversibility of an AE

Possible outcomes of a signal validation are the signal may be

• Validated – Proceeds to further assessment considering all available data
• Non-validated – No further assessment is made
• Inconclusive – Existing data is not sufficient to validate or reject the signal.

Signal prioritization

Signals with significant impact on public health or benefit-risk profile of the drug are prioritized. The time frame for the further management of signal will depend on prioritization. Signal prioritization takes into consideration various aspects of the AE and drug involved in a signal such as

• Severity, seriousness, outcome, reversibility and preventability of an AE
• Patient exposure and frequent of the AE
• Potential of the signal to be applicable to other drugs of same class

Signal assessment

Signal assessment aims at further evaluation of the signal to identify the need for a regulatory action or risk minimization action or further data collection.

This includes review of data from various sources to obtain further information on the signal and to establish causality of the AE with the drug. This takes into consideration various factors such as

• Completeness of the data
• Confounding factors
• Temporal relationship
• Dechallenge and rechallenge information

Signal assessment is an continuous process until there is sufficient evidence to close the signal. The closure of a signal can result in the signal being refuted or any recommendation for action is made.

Recommendations for actions

Recommendations for actions are made for signals that are not refuted during the signal assessment. These recommendations include but not limited to:

• Update of product information
• Further studies – preclinical, clinical or epidemiological
• Additional risk minimization measures
• Periodic review of the safety issue (as an identified or potential risk)
• Regulatory actions (notifying authorities, recall of products etc…)

The timelines for the initiation and completion of the activities are then determined and the actions are executed.

Exchange of information

The exchange of the information regarding the validated signals or the recommendations for actions occurs at various levels such as

• Regulatory authorities
• Health care professionals and patients
• License partners
• Other MAHs of same drug or same class of drug

A successful signal management process is key for the timely identification of the safety issues and mitigating them resulting in a low public health impact and positive benefit-risk profile of the drug. This can abe achieved by following some good practices such as

• Documentation – All the process of signal management should be well documented by the MAH. This includes proper tracking and documentation of the strategy, actions and decisions.
• Transparency – Transparency in terms of signal detection and assessment
• Effective communication – Timely communication of the information to regulatory authorities, HCPs and other MAHs.