RESUMEN
In an ongoing effort to try to understand the variability of QT/QTc data and determine how that variability would affect the design, analysis, and conclusions drawn from data collected in thorough QT/QTc studies, five Pharmaceutical Research and Manufacturers Association (PhRMA) companies recently performed retrospective analyses of placebo and nondrug 12-lead resting electrocardiogram (ECG) data. The data were obtained from five rigorously conducted studies in which the collection and analysis of QT/QTc intervals was a primary objective. Variables that are known to affect variability of QT/QTc intervals, such as adequate resting time before recording the ECGs, food, and consistency of lead placement, had been well controlled in each of the studies. Single ECGs were recorded at each time point, and the QT intervals were measured by ECG laboratories.
Asunto(s)
Industria Farmacéutica , Electrocardiografía/estadística & datos numéricos , Síndrome de QT Prolongado , Placebos , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Proyectos de Investigación/estadística & datos numéricos , Adolescente , Adulto , Análisis de Varianza , Estudios Cruzados , Método Doble Ciego , Industria Farmacéutica/métodos , Industria Farmacéutica/estadística & datos numéricos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Humanos , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/fisiopatología , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
The International Conference on Harmonization (ICH) guidance for clinical evaluation of QT prolongation (E14) affected drug development by advocating that a thorough QT study (TQT) be conducted during development to assess the QT prolongation liability of a compound. The ICH E14 Statistics Group shortly thereafter recommended that a noninferiority intersection-union test (IUT) be used to exclude a clinically worrisome QT prolongation. Recent analyses have indicated that the IUT might be overly conservative with respect to excluding QT prolongation. This report assesses the IUT false positive rate for 4 recently conducted TQT trials using simple simulation experiments. Positive TQT study rates ranged from negligible to nearly 60% depending on study design, sample size, and patient status, despite no drug effect. Addition of clinically nonmeaningful QT prolongations (up to 5 milliseconds) increased the positive study rate to 80% for 1 particular study design. Ultimately, these results reveal significant limitations of the IUT with respect to excluding an effect and study interpretation for certain trial designs.
