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Open Access Research article

Estimating time-to-onset of adverse drug reactions from spontaneous reporting databases

Fanny Leroy12*, Jean-Yves Dauxois3, Hélène Théophile45, Françoise Haramburu45 and Pascale Tubert-Bitter12

Author Affiliations

1 Inserm, CESP Centre for research in Epidemiology and Population Health, U1018, Biostatistics Team, F-94807 Villejuif, France

2 Univ Paris-Sud, UMRS1018, F-94807 Villejuif, France

3 Université de Toulouse-INSA, IMT UMR CNRS 5219, Toulouse, France

4 Département de pharmacologie, Centre de pharmacovigilance, CHU de Bordeaux, Bordeaux, France

5 INSERM U657, Bordeaux, France

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BMC Medical Research Methodology 2014, 14:17  doi:10.1186/1471-2288-14-17

Published: 3 February 2014

Abstract

Background

Analyzing time-to-onset of adverse drug reactions from treatment exposure contributes to meeting pharmacovigilance objectives, i.e. identification and prevention. Post-marketing data are available from reporting systems. Times-to-onset from such databases are right-truncated because some patients who were exposed to the drug and who will eventually develop the adverse drug reaction may do it after the time of analysis and thus are not included in the data. Acknowledgment of the developments adapted to right-truncated data is not widespread and these methods have never been used in pharmacovigilance. We assess the use of appropriate methods as well as the consequences of not taking right truncation into account (naive approach) on parametric maximum likelihood estimation of time-to-onset distribution.

Methods

Both approaches, naive or taking right truncation into account, were compared with a simulation study. We used twelve scenarios for the exponential distribution and twenty-four for the Weibull and log-logistic distributions. These scenarios are defined by a set of parameters: the parameters of the time-to-onset distribution, the probability of this distribution falling within an observable values interval and the sample size. An application to reported lymphoma after anti TNF- α treatment from the French pharmacovigilance is presented.

Results

The simulation study shows that the bias and the mean squared error might in some instances be unacceptably large when right truncation is not considered while the truncation-based estimator shows always better and often satisfactory performances and the gap may be large. For the real dataset, the estimated expected time-to-onset leads to a minimum difference of 58 weeks between both approaches, which is not negligible. This difference is obtained for the Weibull model, under which the estimated probability of this distribution falling within an observable values interval is not far from 1.

Conclusions

It is necessary to take right truncation into account for estimating time-to-onset of adverse drug reactions from spontaneous reporting databases.

Keywords:
Pharmacovigilance; Reporting databases; Right truncation; Parametric estimation; Maximum likelihood estimation; Bias; Simulation study