The scope of the strategy was limited to medicines and vaccines at this stage.

According to the report from the CIOMS Working Group VIII Practical Aspects of Signal Detection in Pharmacovigilance, a signal is defined as “information that arises from one or multiple sources which suggests a potentially new 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.”  WGVIII Report (cioms.ch)

A more recent clarification of the definition provided by the UMC is that a signal “is essentially only a hypothesis [of a causal association between an invention and an event] that, together with data and arguments, justifies the need for further assessment.”  What is a signal? | UMC (who-umc.org)

For the purpose of this strategy, it was agreed to use the definition from UMC, also quoted by the CIOMS Cumulative Glossary with a focus on pharmacovigilance as:

Information on a new or known side effect that may be caused by a medicine and is typically generated from more than a single report of a suspected side effect. It is important to note that a signal does not indicate a direct causal relationship between a side effect and a medicine, but is essentially only a hypothesis that, together with data and arguments, justifies the need for further assessment.

Source: Uppsala Monitoring Centre (UMC). What is a signal?

Regarding the criteria of novelty, it was agreed that a signal would be considered as new if the information is not already mentioned in the product information of SEARN members and some reference NRAs for pharmacovigilance, to be further identified.

The most complete and transparent guidance in signal management has been provided by the EMA in Good Pharmacovigilance Practices IX. A generally applicable interpretation of the steps of signal management includes the following activities: signal detection, signal validation, signal prioritisation, signal assessment and recommendation for action.

Signal detection

Signal detection is the process of looking for and/or identifying signals using data from any source.  Signal detection in passive reporting databases can be done by qualitative (“case-by-case") or quantitative (statistical screening by disproportionality analysis) approaches.

Signal validation

Signal validation is the process of evaluating the data supporting the detected signal in order to verify that the available documentation contains sufficient evidence and therefore justifies further analysis of the signal.  Signal validation should take into account the strength of the evidence, the clinical relevance and the previous awareness of the association.  It can be thought of as a form of preliminary assessment as the extent of evaluation performed during signal validation versus further assessment can vary between individuals/institutions.

The following elements should be considered when performing signal validation based on the review of ICSR data:

• Previous awareness, e.g.:
  • the extent to which information on the adverse reaction is already included in the product information (summary of product characteristics (SmPC) and package leaflet);
  • whether the signal relates to an adverse reaction already included in the SmPC for other medicinal products containing the active substance of interest, bearing in mind that some signals may only be relevant to a specific medicinal product and/or a specific formulation
  • whether the association has already been assessed in the initial application for marketing authorisation, the risk management plan (RMP), the periodic safety update report (PSUR) or any other regulatory procedure, based on information held or known by each organisation;
• Strength of the evidence, taking into account, e.g.:
  • the total number of cases (after exclusion of duplicates), and amongst those, the number of supportive cases, e.g. cases showing a compatible temporal association, positive de- or rechallenge, lack of potential alternative causes, assessed as possibly related by the reporting healthcare professional, with supportive results of relevant investigations;
  • number of cases in the context of patient exposure;
  • additional cases reported with related terms (e.g. other MedDRA terms indicating clinical complications or different stages of the same reaction);
  • consistency of the evidence across cases (e.g. consistent time to onset, pattern with repeated observations of an association); − quality of the data and their documentation;
  • cases matching internationally agreed case definitions if applicable (e.g. Brighton collaboration case definitions for vaccines, RegiSCAR criteria for severe cutaneous adverse reactions);
  • dose-reaction relationship;
  • possible mechanism based on a biological and pharmacological plausibility;
  • disproportionality of reporting, if applicable (see GVP Module IX Add I).
• Clinical relevance and context, e.g.:
  • seriousness and severity of the reaction;
  • outcome and reversibility of the reaction;
  • additional insight on a known adverse reaction, e.g. in terms of its severity, duration, outcome, incidence or management;
  • reactions occurring in the context of drug-drug interactions;
  • reactions occurring in vulnerable populations, children or the older populations, or in patients with pre-existing risk factors;
  • reactions occurring in different patterns of use (e.g. overdose, abuse, misuse, off-label use, medication errors, falsified products);
• Additional sources of information may provide further evidence for or against a causal association, or a new aspect of a known association, and may be considered during further assessment of the signal, depending on their relevance for the signal and availability to each organisation. These may include:
  • clinical trial data;
  • findings regarding similar cases in the scientific literature, including information on substances of the same class of medicinal products;
  • information on the epidemiology of the adverse reaction or the underlying disease; • experimental and/or non-clinical findings;
  • databases with larger datasets, when the signal was detected from national or marketing authorisation holder-specific databases;
  • healthcare databases that may provide information on characteristics of exposed patients and medicines utilisation patterns;
  • information from other regulatory authorities worldwide

Signal prioritisation

Signal prioritisation is the process in which is determined whether a validated signal requires further assessment.  This is based on an initial analysis of the potential impact of the signal on patients’ or public health and the risk-benefit balance of the concerned medicinal product(s).

Three main challenges have been identified in monitoring, detecting, and assessing safety signals at the regional level:

• The legal possibility to share case narratives
• The technical possibility to access case narratives at the regional level
• Insufficient capacity in some countries.

In order to share confidential information, such as case narratives, some countries may need on the short term to sign MoU or confidential disclosure agreement with the IPC.

The monitoring and detection system will be based on the work from the IPC Collaborating Centre, which will identify safety signals for priority products in VigiBase at the regional level:

Priorities

As a first step, it was agreed to prioritize regional collaboration on medicines from the following category:

First step: Priority medicines:

• Public health programmes medicines
• Medicines used widely in the region
• New products

Among these categories, the main objectives of this surveillance programme would be to identify:

• Particularities due to populations/public health systems in the region, including for molecules which are already well known in other parts of the world
• New adverse drug events/new aspects in ADE for new medicines
• Substandard/falsified products with adverse consequences (e.g. due to microbiological or chemical contamination)

On this basis, a list of priority medicines was adopted. In addition, the Assembly recommended to include pregnancy adverse events in the priority list for monitoring /detection at the regional level.

List of priority medicines:

SEARN requested:

• WHO and UMC to explore means to share information (e.g. case narratives) at the regional level.
• SEARN members to consider the WHO core variables for reporting suspected adverse drug event reports and review their national ADR reporting forms as needed.
• SEARN members to share with the IPC Collaborating Centre information about their activities, successes, challenges, etc., which can also be done through sharing their national pharmacovigilance newsletters to provide content for the regional newsletter.