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There is considerable interest in drug safety in many countries, including the US (1). Cardiac safety has assumed a central role in drug safety evaluation for two reasons. Firstly, cardiac adverse drug reactions are typically serious and can be fatal, as was seen for various drugs that were removed from the market in the 1980s and 1990s. Secondly, these fatalities prompted regulatory attention and the development of the ICH Guidelines S7B (2) and E14 (3), released in 2005. These guidelines formalised nonclinical and clinical assessments of an investigative drug’s proarrhythmic liability, and they have been adopted by regulatory agencies in Canada, Europe and the US.
While other cardiac and cardiovascular adverse drug reactions are certainly receiving regulatory attention (4), assessment of proarrhythmic liability remains a central component of preapproval assessments. Recent ‘question and answer’ documents have provided further regulatory commentary on this issue (5-7). This article therefore focuses specifically on the ICH E14 ‘Thorough QT/QTc Study’ or TQT study, a clinical trial dedicated to evaluating a drug’s liability to prolong the QT interval in a tightly controlled environment. It is widely acknowledged that QT interval prolongation is neither a perfect nor the only indicator of a drug’s proarrhythmic liability, but its evaluation is currently required by regulatory agencies.
Following a brief overview of salient characteristics of the QT interval, the design, conduct, statistical analysis, and interpretation of the TQT study are discussed. Statistical aspects are explained in a simplified and relatively succinct manner, with reference made to more detailed sources. |
