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Performance of the Self-Controlled Case Series With Active Comparators for Drug Safety Signal Detection Using the
Astrid Coste1, Angel Y S Wong1, Francois Haguinet2
1LSHTM, Department of Non-Communicable Disease Epidemiology, London, UK.
Pharmacoepidemiology and Drug Safety
|December 12, 2025
Summary
The self-controlled case series (SCCS) method shows moderate performance for drug safety signal detection in UK primary care electronic health records. Active comparators improved specificity but reduced sensitivity, impacting the identification of potential drug risks.
Area of Science:
- Pharmacovigilance and Drug Safety Research
- Real-World Data Analysis in Healthcare
- Epidemiological Methods in Public Health
Background:
- Limited evidence exists on drug safety signal detection using UK primary care electronic health records (EHRs).
- The self-controlled case series (SCCS) method is a promising approach for drug safety signal detection in real-world data.
- Active comparators may enhance SCCS performance by addressing confounding by indication.
Purpose of the Study:
- To evaluate the performance of the SCCS method for signal detection.
- To compare the SCCS method with and without active comparators.
- To utilize the UK Clinical Practice Research Datalink (CPRD) Aurum database for this evaluation.
Main Methods:
- Applied the SCCS method to macrolide and fluoroquinolone antibiotics, using amoxicillin and cefalexin as active comparators.
- Selected seven drugs and 30 outcomes across all organ classes.
- Developed a reference set of 104 positive and 58 negative controls, using a taxonomy framework for suitability.
- Utilized two-year observation periods with a 30-day risk window post-dispensing.
- Measured diagnostic performance using sensitivity and specificity against product labels.
Main Results:
- SCCS without active comparators showed a sensitivity of 0.57 and specificity of 0.77 (2017/2018).
- Active comparators increased specificity to 0.89 but decreased sensitivity to 0.18.
- Five drug-outcome pairs were identified as signals of disproportionality before being listed on product labels.
Conclusions:
- The SCCS method performed moderately well for signal detection in CPRD when using a carefully designed reference set.
- Active comparators effectively reduced confounding by indication but also decreased power and the identification of positive controls.
- The study provided evidence that SCCS can identify safety signals prior to their inclusion on drug labels.
Keywords:
Clinical Practice Research Datalinkpharmacoepidemiologypharmacovigilancereal‐world dataself‐controlled case seriessignal detectionMore Related Videos
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