A New Drug Safety Signal Detection and Triage System Integrating Sequence Symmetry Analysis and Tree-Based Scan Statistics with Longitudinal Data

Abstract

Purpose

Development and evaluation of a drug-safety signal detection system integrating data-mining tools in longitudinal data is essential. This study aimed to construct a new triage system using longitudinal data for drug-safety signal detection, integrating data-mining tools, and evaluate adaptability of such system.

Patients and Methods

Based on relevant guidelines and structural frameworks in Taiwan’s pharmacovigilance system, we constructed a triage system integrating sequence symmetry analysis (SSA) and tree-based scan statistics (TreeScan) as data-mining tools for detecting safety signals. We conducted an exploratory analysis utilizing Taiwan’s National Health Insurance Database and selecting two drug classes (sodium-glucose co-transporter-2 inhibitors (SGLT2i) and non-fluorinated quinolones (NFQ)) as chronic and episodic treatment respectively, as examples to test feasibility of the system.

Results

Under the proposed system, either cohort-based or self-controlled mining with SSA and TreeScan was selected, based on whether the screened drug had an appropriate comparator. All detected alerts were further classified as known adverse drug reactions (ADRs), events related to other causes or potential signals from the triage algorithm, building on existing drug labels and clinical judgement. Exploratory analysis revealed greater numbers of signals for NFQ with a relatively low proportion of known ADRs; most were related to indication, patient characteristics or bias. No safety signals were found. By contrast, most SGLT2i signals were known ADRs or events related to patient characteristics. Four were potential signals warranting further investigation.

Conclusion

The proposed system facilitated active and systematic screening to detect and classify potential safety signals. Countries with real-world longitudinal data could adopt it to streamline drug-safety surveillance.

Keywords:

• drug safety
• signal detection
• triage
• sequence symmetry analysis
• tree-based scan statistics

Abbreviations

ADR, adverse drug reaction; AE, adverse event; CCI, Charlson Comorbidity Index; CIOMS, Council for International Organizations of Medical Sciences; DPP4i, dipeptidyl peptidase-4 inhibitors; FQ, fluoroquinolone; NFQ, non-fluorinated quinolone; NHID, Taiwan’s National Health Insurance Database; PBRER, Periodic Benefit-Risk Evaluation Report; PS, propensity score; RMP, Risk Management Plan; SGLT2i, sodium-glucose co-transporter-2 inhibitors; SR, sequence ratio; SRS, spontaneous reporting systems; SSA, sequence symmetry analysis; TreeScan, tree-based scan statistics.

Data Sharing Statement

The datasets generated and/or analysed during the current study are not publicly available due to legal restrictions governing data privacy protection under Taiwan’s regulations.

Acknowledgments

We are grateful to the Taiwan Food and Drug Administration (TFDA) for providing funding support, and to Dr. Fei-Yuan Sharon Hsiao for assisting in research consultation. We are grateful to Health Data Science Centre, National Taiwan University Hospital and Health Data Science Centre, National Cheng Kung University Hospital for providing administrative and technical support.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

Ms Miyuki Hsing-Chun Hsieh reports grants from Taiwan Food and Drug Administration, during the conduct of the study. Ms Hsun-Yin Liang reports grants from Taiwan Food and Drug Administration, during the conduct of the study. Ms Chih-Ying Tsai reports grants from Taiwan Food and Drug Administration, during the conduct of the study. Ms Yu-Ting Tseng reports grants from Taiwan Food and Drug Administration (TFDA), during the conduct of the study. Mr Pi-Hui Chao reports grants from Taiwan Food and Drug Administration, during the conduct of the study. Ms Wei-I Huang reports grants from Taiwan Food and Drug Administration, during the conduct of the study. Dr Wen-Wen Chen reports grants from Taiwan Food and Drug Administration, during the conduct of the study. The authors declare no other competing interests.

Additional information

Funding

This work was supported by research grants from the Taiwan Food and Drug Administration (TFDA) (MOHW109-FDA-D-113-000411). The content of this article does not represent any official position of the TFDA.