What is Signal Management?

A safety signal is information on a new or known adverse event that may be caused by a human or veterinary medicine and requires further investigation. Within the EEA the European Medicines Agency (EMA), Regulatory Authorities in the EEA Member States, and Marketing Authorisation Holders (MAHS) are collectively responsible for ongoing monitoring to identify case reports of adverse events (AE) or adverse drug reactions (ADR), assess them, identify signals that may potentially require further investigation, and manage the follow-on process.

The presence of a safety signal doesn’t conclusively imply that a medication is the direct cause of the reported adverse event. Other factors, such as an individual’s health condition or other medications they may be taking, could also be contributing factors.

However, when valid safety signals emerge, especially those that could pose a significant public health risk (meaning they are both serious and frequent), they are given top priority for further investigation.

Monitoring is done at least monthly per product with data from the global safety database and clinical databases for non-serious adverse events analysis. Typically, this is from EudraVigilance with Clinical Study data, Individual Case Safety Reports (ICSRS), Aggregate Report data and from Literature Monitoring or other data sources.

There are no specific procedures or rules for investigating potential safety signals and the process is of course based on information available at the time, recognizing that may change.

Expert knowledge and judgment play a crucial role in this ongoing vigilance and assessment process.

Click for more information from the EMA on Signal Management.

Click for more information from the EMA on the relevant GVP module IX.

The signal management process includes the following steps:

Signal Detection.
Signal Evaluation & Validation.
Signal Prioritization.
Signal Assessment.
Recommendation for action.
Exchange of information.

Signal Detection.

Possible safety concerns can be identified through various pharmacovigilance activities, such as:

Ongoing surveillance of adverse events (AEs) and adverse drug reactions (ADRs).
Thorough individual medical reviews of Individual Case Safety Reports (ICSRs).
Reports of product quality complaints.
Compilation of comprehensive aggregate reports like Periodic Safety Update Reports (PSURs).
Risk Management Plan (RMP) for the specific medicinal product.
Continuous monitoring of relevant medical literature.
Data obtained from sponsors of clinical and non-clinical studies.
Information provided by Health Authorities.
Other data or sources that fall within the management or responsibility of the Marketing Authorization Holder (MAH).
Regulatory reports submitted in accordance with regulations.
Data from off-label use of the medication.
Any events that do not meet the criteria for being a reportable (valid) ICSR, but could impact public health or a product’s Benefit-Risk profile are flagged as Emerging Safety Issues.

Signal Evaluation.

The assessment of safety signals is a fundamental component of standard pharmacovigilance practices, essential for providing regulatory authorities with the latest information on the Benefit-Risk profile of a product.

Safety signals are typically evaluated through a combination of methods to evaluate potential signals:

ICSR review.
Comparing historical reporting rates.
Review of incidence rates from previous clinical studies.
Biologic, pharmacokinetic, or pharmacodynamic effects from preclinical studies.
Review of cases with similar events or from similar products in the class.

Signal Prioritization.

The following criteria are used to prioritize signals:

Public health impact.
Significant effect on the benefit-risk profile of the medicinal product.
Patient Impact, depending on severity, reversibility, potential for prevention and clinical outcome of the association.
Consequences of treatment discontinuation on the disease and the availability of other therapeutic options.
Strength and consistency of the supporting evidence.
Clinical context.
Any Marketing Authorisation Application in progress.

Signal Assessment.

Safety signal evaluation aims to delve deeper into the importance and potential risk from a confirmed adverse event signal and identify the necessity for further data collection, risk reduction measures, or regulatory actions.

The following steps will be performed for signal assessment:

Review sources for further information.
Evaluate the importance of a signal on a broader scale, either within the therapeutic context, at the System Organ Class (SOC) level, or using a Standardized MedDRA Query (SMQ).
Document the risk assessment of the signal and recommend further, or no further action.

Recommendation for Action.

Depending on the assessed safety risk and its potential impact on patients, a Drug Safety Physician will proceed to suggest specific actions and review them with the Product Safety Board, which may include but are not limited to:

Initiation of a Health Hazard Assessment (HHA) for possible field action.
Request a Quality Complaint Investigation for further product evaluation.
Expedited reporting to regulatory agencies.
Direct healthcare professional communication.
Updates to safety labeling or prescription information.
Clinical expert statements.
Reporting to investigators, Institutional Review Boards (IRB), Ethics Committees, updating study documents, or holding or stopping ongoing studies early
Continued assessment of the product benefit-risk profile.
Further investigation of the safety risk through additional studies.
Development of a pharmacovigilance plan focused on evaluating the identified risk.
Reporting via periodic report submission.
Risk management document updates.
Additional educational materials or training.

For all validated signals, actions may then be:

Modification of the ongoing monitoring strategy of the product.
Labelling change.
Safety Communications to various parties.
Product recall/correction.
Risk Management Plan update.
Further pharmacovigilance activities.
Additional risk minimization activities
A Post-Authorization Safety Study (PASS)
Periodic signal review.

Exchange of Information.

A Safety Physician will also:

Immediately communicate any validated signal with an implication for public health or significant effect on the benefit-risk profile to regulatory authorities as an Emerging Safety Issue.
Depending on severity, communicate a validated signal, or a new aspect of a known risk, which does not have implications for the benefit-risk profile to regulatory authorities.
Communicate the outcome of the signal assessment if it involves a new or changed risk to the public, health care professionals, patients and the MAH.

Veterinary Signal Management.

As for human medicinal products, Signal Management also applies to Veterinary Pharmacovigilance, and the responsibilities, processes and activities are largely the same, however reporting on them is done on an annual basis, via the IRIS platform for Veterinary Medicinal Products (VMPs).

Data still comes from sources such as spontaneous reports, clinical studies, and Literature Monitoring, and from the EVVet database.

Click for more information from the EMA on Signal Management for Veterinary Medicines.

Click for more information from the EMA on Veterinary good pharmacovigilance practices (VGVP).

Why use Aegisana’s Signal Management services?

Efficient and thorough.

Aegisana’s Pharmacovigilance experts have extensive expertise in promptly detecting and processing Signals for both investigational and authorized medicinal products.

Our in-house monitoring systems can diligently evaluate information from diverse channels to provide comprehensive updates, including any potential implications to your Benefit-Risk profile, to your product safety team and relevant stakeholders, ensuring your compliance and the well-being of patients.

Compliance without surprises.

Your peace of mind comes from the assurance that your system is compliant and well-prepared for inspections, free from unexpected issues, and equipped with effective communication procedures.

Regardless of the complexity of your needs, we can offer efficient tailored solutions that instill your unwavering confidence in our capacity to deliver.