What is QT Analysis?
Some drugs that are not designed to affect the heart can have dangerous consequences. Some of these include, delay cardiac repolarization and increase the 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. 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 This requirement is a result of several drugs (e.g., terfenadine) that had to be withdrawn from the market due to unexpected cases of TdP.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, or TQT; it is often expensive (to the tune of $5 million dollars to conduct and interpret) and can delay time to market by a year or more.
C-QT May Eliminate 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 (approved by the International Council for Harmonisation E14), Nuventra can help establish the risk of prolonging the QT interval and possibly avoid a TQT study completely. A C-QT analysis is a low-cost and efficient service compared to running a TQT study.
In a C-QT analysis, pharmacokinetic 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 12-lead ECG data is obtained from clinical studies that have already been collected, or that will be collected. 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 from therapeutic and supra-therapeutic doses, then companies can apply for a TQT waiver, which indicates that the FDA recognizes that they do not have to conduct a full TQT study. Things that can affect if a TQT is waived 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 contribute to allow the more efficient design of a TQT study.
How Does Concentration-QT Analysis Work?
Nuventra matches up the PK Data and the ECG Data collected in standard clinical studies, including first time in human (FTIH), single ascending dose, multiple ascending dose, proof of concept phase 2, or any combination. These standard clinical studies are required for drug development and can be used to address if a TQT is needed.
Nuventra can help plan the best study design to obtain 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 obtained, we use industry-standard software (NONMEM) and apply proven techniques to generate a quality C-QT analysis and report that can be submitted directly to the FDA.
Note that Concentration-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 Concentration-QT Analysis. However, you can conduct Concentration-QT Analysis on legacy studies as well.
A FDA-approved C-QT analysis costs approximately $150,000 to $300,000 to assess QT/QTc prolongation and can be used to obtain a regulatory waiver for the 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. Learn more about how PK/PD analysis can potentially eliminate the need for a TQT study on our blog.
Contact one of our senior consultants and industry-veteran pharmacometricians to learn how Nuventra can support your drug development program with a C-QT analysis.