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Drug Safety

, Volume 33, Issue 5, pp 417–434 | Cite as

Modelling the Time to Onset of Adverse Reactions with Parametric Survival Distributions

A Potential Approach to Signal Detection and Evaluation
  • François MaignenEmail author
  • Manfred Hauben
  • Panos Tsintis
Original Research Article
First Online:

Abstract

Background: It has been postulated that the time to onset of adverse drug reactions is connected to the underlying pharmacological (or toxic) mechanism of adverse drug reactions whether the reaction is time dependent or not.

Objective: We have conducted a preliminary study using the parametric modelling of the time to onset of adverse reactions as an approach to signal detection on spontaneous reporting system databases.

Methods: We performed a parametric modelling of the reported time to onset of adverse drug reactions for which the underlying toxic mechanism is characterized. For the purpose of our study, we have used the reported liver injuries associated with bosentan, and the infections associated with the use of the tumour necrosis factor (TNF) inhibitors, adalimumab, etanercept and infliximab, which are used in Crohn’s disease and rheumatoid arthritis, reported to EudraVigilance between December 2001 and September 2006.

Results: The main results reflect the fact that the reported time to onset is a surrogate of the true time to onset of the reaction and combines three hazards (occurrence, diagnosis and reporting) that cannot be disentangled. Consequently, the modelling of the time to onset of reactions reported with TNF inhibitors showed differences that could reflect different pharmacological activities, indications, monitoring of the patients or different reporting patterns. These variations could also limit the interpretation of the parametric modelling.

Conclusions: Some consistency that was found between the occurrences of the infections with the TNF inhibitors suggests a causal association. There are statistical issues that are important to keep in mind when interpreting the results (the impact of the data quality on the fit of the distributions and the absence of a test of hypothesis linked to the absence of a relevant comparator). The study suggests that the modelling of the reported time to onset of adverse reactions could be a useful adjunct to other signal detection methods.

Keywords

Infliximab Etanercept Adverse Drug Reaction Adalimumab Hazard Function 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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Notes

Acknowledgements

No external source of funding was used to perform this study. The implementation of EudraVigilance was undertaken by the EudraVigilance team at the European Medicines Agency led by Dr Sabine Brosch. F. Maignen has no conflicts of interest relevant to this study to declare (declaration of interest available from European Medicines Agency). P. Tsintis contributed to the study when he was working for the European Medicines Agency. M. Hauben is a full-time employee in the Risk Management Strategy Department, Pfizer Inc., New York, NY, USA. He also holds faculty appointments in the Department of Medicine at New York University School of Medicine, New York, NY, USA; the Department of Family and Community Medicine and the Department of Pharmacology, New York Medical College, Valhalla, NY, USA; and the School of Information Systems, Computing and Mathematics, Brunel University, London, England. M. Hauben owns stock and stock options in Pfizer Inc. He also owns stocks in other pharmaceutical companies that may manufacture/market medicinal products mentioned in this study or that may compete with products mentioned in this study. For confidentiality reasons, M. Hauben did not access the raw data used to perform this study.

None of the authors have any conflicts of interest with any statistical software provider. Valuable comments on this work were received from Nils Feltelius, Hans-Georg Eichler, Francesco Pignatti, Xavier Kurz, Jim Slattery and Anders Sundström. In addition, the comments received from the anonymous peer reviewers have greatly improved the quality of the manuscript.

The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties.

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Copyright information

© Adis Data Information BV 2010

Authors and Affiliations

  • François Maignen
    • 1
    Email author
  • Manfred Hauben
    • 2
  • Panos Tsintis
    • 3
  1. 1.Pharmacovigilance and Risk Management SectorEuropean Medicines AgencyLondonUK
  2. 2.EudraVigilance Expert Working GroupLondonUK
  3. 3.EMASHitchinUK

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