A Comprehensive Methodology to Systematically Identify Drug Hypersensitivity and Anaphylactic Reactions in Clinical Tria
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ORIGINAL RESEARCH ARTICLE
A Comprehensive Methodology to Systematically Identify Drug Hypersensitivity and Anaphylactic Reactions in Clinical Trial Databases Hugo Xavier1 · Indira Hara2 · Lone H. Ottesen1 · Remy B. Verheijen1 · Dana Ghiorghiu1 · Claire Morgan3
© Springer Nature Switzerland AG 2020
Abstract Background The incidence of drug hypersensitivity or anaphylactic reactions in clinical trial databases is thought to be underestimated due to variable clinical presentations and lack of clear definitions. Objective Our objective was to develop a more comprehensive, systematic methodology for retrospectively identifying potential hypersensitivity or anaphylactic reactions reported in patients treated with investigational drugs in clinical trials and to accurately assess and characterise the risk. Methods A three-step approach was developed to identify hypersensitivity or anaphylactic reactions: clinical trial database search, medical review, and adjudication to confirm or rule out cases. The database search strategy consisted of the narrow search for Standardized MedDRA Query (SMQ) Hypersensitivity, a modified MedDRA query based on SMQ Anaphylactic reaction, and pyrexia-related MedDRA Preferred Terms. The cases identified from the search were further medically reviewed taking into consideration the temporal relationship, seriousness, severity, course, and management of the events, action taken, and outcomes of adverse events. Those cases deemed to have potentially drug-related hypersensitivity were then adjudicated to be confirmed or ruled out. Results The method was applied to a clinical trial database containing safety data for 421 patients treated with an investigational drug. Application of the methodology led to 19 hypersensitivity cases being identified. Of these, 12 were classified as immediate reactions and 7 as non-immediate reactions. Conclusion This three-step method provided a thorough and robust way to identify hypersensitivity reactions, including anaphylaxis, in a clinical trial database. This method could be applied to investigational drugs to improve early detection and monitoring of potential safety concerns, subsequent patient safety management strategies, and potentially programme-wide drug development decisions. Algorithmic tools and narrow and/or broad SMQs should be considered when evaluating safety concerns. The authors also recommend a revision of the MedDRA SMQ of Anaphylactic reaction.
1 Introduction Drug-induced hypersensitivity reactions are unpredictable and are typically divided into immune-mediated or allergic and non-immune-mediated or pseudo-allergic reactions [1, 2]. The variability of the clinical presentation of drug hypersensitivity reactions can mean that they may be overlooked by a treating physician seeing only a few patients with the * Claire Morgan [email protected] 1
Research and Development, AstraZeneca, Cambridge, UK
2
Patient Safety, Medimmune-AstraZeneca, Cambridge, UK
3
Global Patient Safety, AstraZeneca, One Medimmune Way, Gaithersb
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