Biases affecting the proportional reporting ratio (PPR) in spontaneous reports pharmacovigilance databases: the example of sertindole.
BACKGROUND
Automated measures of reporting disproportionality in databases of spontaneous reports of adverse drug reactions are an emerging tool to identify drug-related alerts. Sertindole, a new atypical neuroleptic known to prolong the QT interval, was suspended in November 1998 because the proportion of reports of fatal reactions suggesting arrhythmia among all reports with sertindole was almost ten times higher than that for other atypical neuroleptics in the UK. This excess risk was not predicted in preclinical data and had not been found in premarketing trials.


METHODS
Reporting patterns over time were analysed. Prescription Event Monitoring (PEM) studies and a large retrospective cohort allowed for the comparison of actual death rates with atypical neuroleptics, and to assess which proportion of the deaths that occurred were reported.


RESULTS
There were indications of possible skewing of reporting related to notoriety, surveillance and market size effects. Death rates in PEM studies were essentially similar between sertindole and other neuroleptics. Cardiac deaths had been two to three times more often reported than other causes of death.


CONCLUSIONS
Proportional reporting ratios indicate differential reporting of possible reactions, not necessarily differential occurrence. There was no indication of an actual increase of risk of all causes or cardiac deaths during sertindole treatment, but only an increased risk of its being reported. The suspension of sertindole was rescinded by Committee on Proprietary Medicinal Products (CPMP) in October 2001.
Moore
Nicholas
N
Département de Pharmacologie, Université Victor Segalen-Bordeaux 2, BP36, 33076 Bordeaux, France. nicholas.moore@pharmaco.u-bordeaux2.fr
Hall
Gillian
G
Sturkenboom
Miriam
M
Mann
Ron
R
Lagnaoui
Rajaa
R
Begaud
Bernard
B
D016907:Adverse Drug Reaction Reporting Systems / Q000458:organization & administration*; D014150:Antipsychotic Agents / Q000009:adverse effects*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000401:mortality; D015982:Bias; D016001:Confidence Intervals; D016903:Drug Monitoring / Q000379:methods*; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects*; D007211:Indoles / Q000009:adverse effects*; D015203:Reproducibility of Results; D006113:United Kingdom
D014150:Antipsychotic Agents; D007093:Imidazoles; D007211:Indoles; C066304:sertindole