IX.B.3. Evaluation during signal validation and further assessment

Location:
IX.B.

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 (see IX.A.1.1.);
    • 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 (see GVP P.I.), RegiSCAR criteria for severe cutaneous adverse reactions (10)); − 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 (e.g. pregnant women (see GVP P.III.), children (see GVP P.IV.) or the older population (see GVP P. V.)) 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 (see IX.B.1.), 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.

Within individual organisations, the signal management process may involve several rounds of expert discussions and different levels of decision-making. This may result in various decisions, as shown in the example in Figure IX.1. (see also IX.C.4.). Any such decision tree should be documented as part of the description of the signal management process (see IX.B.5.).