Listedness refers to the classification of a suspected adverse drug reaction based on the company’s Company Core Safety Information. It determines whether the reaction is described as known within this information and thus serves to characterize a case. However, for expedited reporting, listedness according to ICH E2D is not the applicable criterion.
Reference Document: The Core Safety Information
The Company Core Safety Information is the safety-related part of the Company Core Data Sheet. The comparison does not merely check whether a similar term appears somewhere in a product document. The case description is compared with the company’s Core Safety Information in terms of nature, severity, specificity, and outcome, so that its listedness can be consistently classified.
This characterization is helpful for internal safety assessment because global case series and safety evaluations can work with a common reference. It can reveal whether a case is consistent with the centrally maintained safety position or concerns a manifestation not previously included. The result, along with the version used and the medical rationale, should be traceable in the case file.
Listedness is therefore not a statement that a causal relationship has been proven or disproven. It exclusively describes the relationship of a reaction to a specific company reference information. Causality assessment, severity grading, and the review of regulatory expectedness address different questions and, if applicable, different documents.
Expectedness and Local Product Information
The expectedness of an adverse drug reaction is checked against the local or regional product information, such as the Summary of Product Characteristics (SmPC) or package leaflet. ICH E2D defines an unexpected adverse drug reaction as a reaction whose nature, severity, specificity, or outcome does not align with the term or description used therein. This local reference is important for determining whether the criteria for expedited reporting are met.
This distinction is particularly relevant when the global Core Safety Information and the local product information are not identical. A reaction may be listed in the Company Core Safety Information but still be considered unexpected in the respective local market. Conversely, a general assumption about the effects of a drug class should not replace specific mention for the affected product.
In cases of uncertainty regarding expectedness, the reaction should be treated as unexpected according to ICH E2D. For a fatal reaction, it must additionally be checked whether the local or regional product information explicitly describes this outcome as possible. These decisions are part of the expectedness assessment; they cannot be preempted by the label “listed.”
Distinction: Listedness is not Expectedness
Listedness and expectedness are often conflated in daily work because both require a comparison with safety information. However, they differ in their reference document and function. Listedness characterizes the adverse reaction according to the Company Core Safety Information; expectedness checks the local or regional product information.
For expedited reporting, listedness is not applicable according to ICH E2D. Key factors include expectedness and other case criteria. Excluding an expedited reportable case solely because the event is listed in the global Core Safety Information confuses two assessments with different regulatory consequences.
The existing entry suspected-unexpected-serious-adverse-reaction includes the characteristic “unexpected.” This characteristic does not arise from listedness. A SUSAR assessment links severity, suspected causality, and unexpectedness according to the relevant reference information; listedness can additionally be documented for global safety characterization.
Relevance for clinical trials
For investigational medicinal products and approved drugs in studies, teams must clearly define which reference information applies to which safety decision. Incorrect assignment can lead to inconsistencies in medical assessment, narrative, or communication with investigators. Versioned safety references, documented comparison decisions, and the escalation of disputed cases to medical professionals are therefore crucial work steps.
Full-service CROs like Mediconomics support the listedness review by maintaining version-controlled reference documents, case-specific documentation of comparisons and rationales, and coordination between Case Processing and Medical Safety. They can also transparently track differences between global Core Safety Information and local SmPCs for Regulatory Affairs, Investigator Brochures, and safety narratives.
Frequently Asked Questions (FAQ)
Can a listed reaction still be unexpected?
Yes. Listedness refers to the Company Core Safety Information, while expectedness refers to the local or regional product information. If the two references do not align, the results may differ.
Does listedness determine expedited reporting?
No. ICH E2D states that listedness is not applicable for expedited reporting. It serves for characterization, while expectedness must be assessed against the relevant product information.
Is a reference to a drug class sufficient for expectedness?
Not without further consideration. A class effect is only to be classified as expected for the drug in question if the local or regional product information describes it accordingly for that product.
Regulatory References
- ICH E2D, Post-Approval Safety Data Management – distinguishes listedness from expectedness.
- ICH E2A, Clinical Safety Data Management – contains the international framework for expedited safety reporting.
- GVP Module VI, Management and reporting of adverse reaction reports – addresses the processing and evaluation of individual cases.
- GVP Module VII, Periodic Safety Update Report – integrates reference safety information into periodic assessments.