An R package for industrializing concentration-QT analysis
Tobias Sing, Martin Fink, Michael Looby
Novartis Pharma AG
Objectives:Since 2005, the FDA recommends a dedicated study (Thorough QT; tQT) to be conducted for every NME to determine the effect of the drug on the QT interval in healthy volunteers. The current regulatory opinion on the design and analysis of tQT studies is formulated in the ICH E14 guideline . The purposes of this package are: (1) to provide a set of R functions that can be used flexibly to visualize, analyze, and model (concentration-) ECG data from a clinical study (tQT or other); (2) to provide a "one-click" approach to perform a standardized, pre-specified analysis; (3) to automate the creation of analysis datasets from clinical databases; (4) to automate the insertion of analysis results into a Word template report for concentration-QT analyses.
Methods:The package was implemented in R and only relies on nlme (linear/nonlinear mixed-effects modeling) as an additional package.
Results:The package contains functions to perform all the steps of a typical (concentration-) QT analysis, including: correcting QT for variation in the RR interval; performing baseline- and placebo correction; exploratory graphics; point-wise t-test according to E14 guideline with graphical presentation; pre-implemented exposure-QT models (extensible by user); tabular and graphical model summaries and diagnostics; nonparametric bootstrap to assess uncertainty of population prediction for any linear or nonlinear mixed-effects model; visual predictive check.
Conclusions:The QT package for R facilitates, speeds up, and industrializes the analysis of ECG data from clinical studies. A standardized, pre-specified analysis can be performed with a single command. Alternatively, the user can also tailor analyses to their specific needs by using the functions of the package individually. All functions can also be modified and extended within R.
ICH E14 Guideline (2005): Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs.