Most pharmacovigilance departments maintain a system to identify adverse drug reactions (ADRs) through analysis of spontaneous reports. The signal detection algorithms (SDAs) and the nature of the reporting databases vary between operators and it is unclear whether any algorithm can be expected to provide good performance in a wide range of environments.
The objective of this study was to compare the performance of commonly used algorithms across spontaneous reporting databases operated by pharmaceutical companies and national and international pharmacovigilance organisations.
220 products were chosen and a reference set of ADRs was compiled. Within four company, one national and two international databases, 15 SDAs based on five disproportionality methods were tested. Signals of disproportionate reporting (SDRs) were calculated at monthly intervals and classified by comparison with the reference set. These results were summarised as sensitivity and precision for each algorithm in each database.
Different algorithms performed differently between databases but no method dominated all others. Performance was strongly dependent on the thresholds used to define a statistical signal. However, the different disproportionality statistics did not influence the achievable performance. The relative performance of two algorithms was similar in different databases. Over the lifetime of a product there is a reduction in precision for any method.
In designing signal detection systems, careful consideration should be given to the criteria that are used to define an SDR. The choice of disproportionality statistic does not appreciably affect the achievable range of signal detection performance and so this can primarily be based on ease of implementation, interpretation and minimisation of computing resources. The changes in sensitivity and precision obtainable by replacing one algorithm with another are predictable. However, the absolute performance of a method is specific to the database and is best assessed directly on that database. New methods may be required to gain appreciable improvements.
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To avoid confusion it should be noted that an SDR does not necessarily fulfil the requirements of a signal as defined in pharmacovigilance.
MedDRA® (the Medical Dictionary for Regulatory Activities) terminology is the international medical terminology developed under the auspices of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). MedDRA® trademark is owned by the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) on behalf of ICH.
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We would like to thank Jenny Wong, Jeffery Painter, Ramin Arani, Niklas Noren, Phil Tregunno, Michael Kayser and Magnus Lerch for their part in the study and constructive comments. The views expressed in this paper are those of the authors only and do not reflect the official policy or position of the IMI JU (Innovative Medicines Initiative Joint Undertaking), the European Union, European Federation of Pharmaceutical Industries and Associations (EFPIA) or the Medicines and Healthcare products Regulatory Agency.
Conflicts of interest
The PROTECT project has received support from the Innovative Medicine Initiative Joint Undertaking (http://www.imi.europa.eu) under Grant Agreement No. 115004, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in kind contribution. Gianmario Candore, Kristina Juhlin, Katrin Manlik, Bharat Thakrar, Naashika Quarcoo, Suzie Seabroke, Antoni Wisniewski and Jim Slattery have no financial interest in any commercial signal detection software. Katrin Manlik is an employee of Bayer Pharma AG, Bharat Thakrar is an employee of Roche and holds shares in both Roche and GlaxoSmithKline, Naashika Quarcoo is an employee of and holds shares in GlaxoSmithKline, and Antoni Wisniewski is an employee of and holds shares in AstraZeneca. Products from these companies were among those used to test the methodologies in this research.
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Candore, G., Juhlin, K., Manlik, K. et al. Comparison of Statistical Signal Detection Methods Within and Across Spontaneous Reporting Databases. Drug Saf 38, 577–587 (2015). https://doi.org/10.1007/s40264-015-0289-5
- Reporting Odds Ratio
- Proportional Reporting Ratio
- Uppsala Monitoring Centre
- Spontaneous Reporting Database
- Disproportionate Reporting