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Computing limits on medicine risks based on collections of individual case reports
Stockholm University, Faculty of Social Sciences, Department of Computer and Systems Sciences. Uppsala Monitoring Centre, Sweden.
Stockholm University, Faculty of Science, Department of Mathematics. Uppsala Monitoring Centre, Sweden.
2014 (English)In: Theoretical Biology Medical Modelling, ISSN 1742-4682, E-ISSN 1742-4682, Vol. 11, 15Article in journal (Refereed) Published
Abstract [en]

Background: Quantifying a medicine's risks for adverse effects is crucial in assessing its value as a therapeutic agent. Rare adverse effects are often not detected until after the medicine is marketed and used in large and heterogeneous patient populations, and risk quantification is even more difficult. While individual case reports of suspected harm from medicines are instrumental in the detection of previously unknown adverse effects, they are currently not used for risk quantification. The aim of this article is to demonstrate how and when limits on medicine risks can be computed from collections of individual case reports. Methods: We propose a model where drug exposures in the real world may be followed by adverse episodes, each containing one or several adverse effects. Any adverse episode can be reported at most once, and each report corresponds to a single adverse episode. Based on this model, we derive upper and lower limits for the per-exposure risk of an adverse effect for a given drug. Results: An upper limit for the per-exposure risk of the adverse effect Y for a given drug X is provided by the reporting ratio of X together with Y relative to all reports on X, under two assumptions: (i) the average number of adverse episodes following exposure to X is one or less; and (ii) adverse episodes that follow X and contain Y are more frequently reported than adverse episodes in general that follow X. Further, a lower risk limit is provided by dividing the number of reports on X together with Y by the total number of exposures to X, under the assumption that exposures to X that are followed by Y generate on average at most one report on X together with Y. Using real data, limits for the narcolepsy risk following Pandemrix vaccination and the risk of coeliac disease following antihypertensive treatment were computed and found to conform to reference risk values from epidemiological studies. Conclusions: Our framework enables quantification of medicine risks in situations where this is otherwise difficult or impossible. It has wide applicability, but should be particularly useful in structured benefit-risk assessments that include rare adverse effects.

Place, publisher, year, edition, pages
2014. Vol. 11, 15
Keyword [en]
Pharmacovigilance, Pharmacoepidemiology, Benefit-risk, Risk-benefit, Adverse drug reactions, Adverse drug reaction surveillance, Post-marketing, Post-marketing surveillance, Spontaneous reports
National Category
Mathematics Bioinformatics (Computational Biology)
Research subject
Computer and Systems Sciences
URN: urn:nbn:se:su:diva-103987DOI: 10.1186/1742-4682-11-15ISI: 000334626600002OAI: diva2:720888


Available from: 2014-06-02 Created: 2014-05-27 Last updated: 2015-11-16Bibliographically approved
In thesis
1. Quantitative methods to support drug benefit-risk assessment
Open this publication in new window or tab >>Quantitative methods to support drug benefit-risk assessment
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Joint evaluation of drugs’ beneficial and adverse effects is required in many situations, in particular to inform decisions on initial or sustained marketing of drugs, or to guide the treatment of individual patients. This synthesis, known as benefit-risk assessment, is without doubt important: timely decisions supported by transparent and sound assessments can reduce mortality and morbidity in potentially large groups of patients. At the same time, it can be hugely complex: drug effects are generally disparate in nature and likelihood, and the information that needs to be processed is diverse, uncertain, deficient, or even unavailable. Hence there is a clear need for methods that can reliably and efficiently support the benefit-risk assessment process. For already marketed drugs, this process often starts with the detection of previously unknown risks that are subsequently integrated with all other relevant information for joint analysis.

In this thesis, quantitative methods are devised to support different aspects of drug benefit-risk assessment, and the practical usefulness of these methods is demonstrated in clinically relevant case studies. Shrinkage regression is adapted and implemented for large-scale screening in collections of individual case reports, leading to the discovery of a link between methylprednisolone and hepatotoxicity. This adverse effect is then considered as part of a complete benefit-risk assessment of methylpredniso­lone in multiple sclerosis relapses, set in a general framework of probabilistic decision analysis. Two methods devised in the thesis substantively contribute to this assessment: one for efficient generation of utility distributions for the considered clinical outcomes, driven by modelling of qualitative information; and one for computing risk limits for rare and otherwise non-quantifiable adverse effects, based on collections of individual case reports.

Place, publisher, year, edition, pages
Stockholm: Department of Computer and Systems Sciences, Stockholm University, 2014. 94 p.
Report Series / Department of Computer & Systems Sciences, ISSN 1101-8526 ; 14-001
National Category
Information Systems
Research subject
Computer and Systems Sciences
urn:nbn:se:su:diva-100286 (URN)978-91-7447-856-3 (ISBN)
Public defence
2014-03-21, Sal C, Forum 100, Isafjordsgatan 39, Kista, 10:00 (English)

At the time of the doctoral defence the following papers were unpublished and had a status as follows: Paper 6: Manuscript; Paper 7: Manuscript.

Available from: 2014-02-27 Created: 2014-01-31 Last updated: 2015-11-16Bibliographically approved

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