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Evaluating drug toxicity signals: is a hierarchical classification of evidence useful or a hindrance?
Author(s) -
van Staa T. P.,
Smeeth L.,
Persson I.,
Parkinson J.,
Leufkens H. G. M.
Publication year - 2008
Publication title -
pharmacoepidemiology and drug safety
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.023
H-Index - 96
eISSN - 1099-1557
pISSN - 1053-8569
DOI - 10.1002/pds.1568
Subject(s) - medicine , drug , pharmacoepidemiology , pharmacology , toxicity , computational biology , medical prescription , biology
Purpose Only randomized clinical trials (RCTs) are deemed suitable to determine causality, as epidemiological studies are considered not ‘robust’. The objective of this study was to evaluate whether causality should remain the only consideration with drug toxicity signals. Cyclooxygenase‐2 (Cox‐2) inhibitors provided an example. Methods Our study population included patients aged 40+ years prescribed Cox‐2 inhibitors in the General Practice Research Database (GPRD) ( N = 150 000). We estimated the risks of upper gastrointestinal (GI) events and myocardial infarction (MI). Attributable risks were estimated using simulation methodology based on various hypothetical scenarios. Results The risk–benefit profile was strongly related to the rate of GI events. With a RCT incidence, the GI benefits would exceed MI risks. With a ‘real‐life’ GI incidence, the benefits did not exceed the risks substantially. The onset and offset of drug effects also predicted the magnitude of both risks and benefits. If risks and benefits occurred in different sub‐groups, the risk–benefit profile varied substantially. Also, it was found that any restriction of use to patients at high risk of drug toxicity may not improve the risk–benefit profile when this restriction affected patients who would benefit most. Conclusions We conclude that rigid classification of evidence is not appropriate in the monitoring of risks and benefits and all valid study evidence—not only that derived from a RCT— needs to be included. The first priority should be to consider the potential impact of a drug toxicity signal. Copyright © 2008 John Wiley & Sons, Ltd.