Some drugs that are not designed to affect the heart can have dangerous consequences. Some of these include, delayed cardiac repolarization and increased risk for dangerous cardiac arrhythmias, including torsade de pointes (TdP). The risk for undesirable heart effects can often be identified early in clinical development by analysis of a patient’s electrocardiogram (ECG), a test that records the electrical activity of the heart.
What is QT Analysis?
Increased risk for TdP and other arrhythmias can be noted by a longer QT interval on an ECG; since the QT interval is a representation of the time of ventricular activity. This includes both depolarization and repolarization – a longer QT interval indicates longer (delayed) repolarization and risk for arrhythmia.
Today, the FDA requires drug developers to conduct studies for any new drug to see if there is an increased risk for QT prolongation. This requirement is a result of several drugs (e.g., terfenadine) that had to be withdrawn from the market due to unexpected cases of TdP. In an effort to reduce risk to patients, regulatory agencies now require rigorous analysis of QT intervals in clinical trials as a measure of drug safety. This rigorous analysis is known as Thorough QT analysis (TQT). TQT studies can cost upwards of $5 million dollars to conduct and interpret and can delay time to market by a year or more.
Eliminating the Need for a TQT Study
PK/PD modeling and simulation techniques can sometimes eliminate the need for a TQT study. Using an internationally accepted approach called Concentration-QT (C-QT) analysis, Nuventra can establish the risk of prolonging the QT interval and possibly avoid a full TQT study. The C-QT analysis approach has been approved by the International Council for Harmonisation E14 and is a low-cost and efficient service compared to running a TQT study.
In a C-QT analysis, pharmacokinetic (PK) data (concentration of a drug over time) is time matched with ECG or EKG data to create a measure of exposure and response. The PK and ECG data is collected from clinical studies that have already been planned or completed. Our team then performs exposure-responses modeling techniques, using the amount of drug as the “exposure” and QT interval as the “response.”
If valid data are available, then companies can apply for a TQT waiver. If the TQT waiver is approved by the FDA it means you do not have to conduct a full TQT study. Factors that can affect a TQT waiver approval include how much information is available at supra-therapeutic doses, expectations from drug interactions, how the QT data were collected (e.g., triplicate vs single readings, manual vs computerized readings), and whether or not there is an effect of the drug on the heart rate. If a TQT study is still required after a C-QT analysis has been completed, the data can help make the TQT study design more efficient.
Nuventra matches up PK and ECG data collected in standard clinical studies that are already required for drug development. Our scientists help create the best study design possible to obtain the right data for a C-QT analysis (e.g., wide dose range, matching PK and ECG collection times, triplicate ECG readings, etc.). Once the data has been collected, we use industry-standard software and proven techniques to generate a high-quality C-QT analysis and report that can be submitted directly to the FDA.
It is important to note that C-QT analyses are only as good as the data collected during clinical development. Nuventra strongly recommends engaging with a team of experts prior to executing any studies that will support a C-QT analysis. However, you can conduct C-QT analysis on legacy studies as well. A C-QT analysis costs approximately $150,000 to $300,000 compared to a TQT study, which can cost upwards of $5 million to conduct and interpret. C-QT analyses can also be completed in a quarter of the time that a thorough TQT study would take.
PK/PD modeling and simulation techniques can sometimes eliminate the need for a TQT study. Our C-QT services include:
- Planning study designs that best support C-QT analysis
- Using NONMEM to generate quality C-QT analysis
- Creating final submission-ready reports
- Using a completed C-QT analysis to design a more efficient TQT analysis, if needed
Learn more about how PK/PD analysis can potentially eliminate the need for a TQT study on our blog. Contact one of our industry-veteran pharmacometricians to learn how Nuventra can support your drug development program with a C-QT analysis.