PK/PD Analysis Potentially Eliminates the Need of a Thorough QT QTc Study
October 18, 2015
As part of each drug development program, the FDA will need to know if a drug prolongs the heartbeat interval (called QT/QTc prolongation). Typically, this assessment is made by conducting a thorough QT (TQT) clinical study that can cost millions of dollars and take upwards of 1 year to complete. Using a pharmacokinetic (PK) and pharmacodynamic (PD) approach called a "concentration-QT" or "C-QT" Analysis, Allucent can help establish the risk of QT prolongation and potentially avoid the expense of conducting a thorough QT study.
C-QT Analysis is an FDA-accepted technique that matches pharmacokinetic (PK) data (concentration of a drug over time) with ECG/EKG data from clinical studies and uses a technique called "exposure-response." Here, the "exposure’" is the amount of drug in the body which is correlated to the "response" or the ECG data (QT interval). If the concentration-QT Analysis is ‘negative’ (i.e., no effect on cardiac repolarization) then a thorough QT clinical study is not needed.
How Does Allucent Use Concentration-QT Analysis?
Allucent matches up the PK data and the ECG data collected in standard clinical studies, such as any combination of first-in-human (FIH), single ascending does (SAD), multiple ascending does (MAD), or proof of concept phase 2. These standard clinical studies have to be conducted regardless, but the thorough QT (TQT) study does not. Allucent can combine volunteer and patient data that have both PK and ECG measures to conduct the analysis. We use industry-standard software (NONMEM) and apply proven techniques that have been used to support the approval of countless drugs on the market.
The key is to design studies that are already planned in a way that ensures they will obtain the best data to conduct a concentration-QT analysis (e.g., wide dose range, matching PK and ECG collection times, etc.). NOTE: Concentration-QT analyses are only as good as the data collected during clinical development. We strongly recommend contacting Allucent prior to conducting any studies that will support a concentration-QT analysis, if possible. However, we have had great experience conducting concentration-QT analysis on legacy studies as well.
Thorough QT (TQT) Study vs. Concentration-QT (cQT) with PK/PD Analysis
PK/PD Analysis could potentially eliminate the cost of a thorough QT/QTc study resulting in millions of dollars in savings during drug development. A thorough QT (TQT) study costs between $2 million and $4 million to conduct, interpret, and report. Allucent uses an FDA-accepted PK/PD technique, called concentration-QT analysis (cQT) to assess the QT/QTc prolongation that is usually determined during a TQT study.
Allucent's PK/PD analysis could potentially eliminate the need to conduct a TQT study altogether. Using the C-QT analysis and PK/PD technique, Allucent analyzes the pharmacokinetics (concentration) of the drug relative to ECG/EKG data (QT, pharmacodynamics) collected in already planned or already executed standard clinical studies for drug development programs. Concentration-QT analysis uses standard PK/PD modeling and simulation techniques (called exposure-response or E-R) to assess the potential of a drug in delaying cardiac re-polarization. These techniques are used in all other drug programs, are readily accepted by the FDA, and have supported the approval of countless drugs currently on the market.
If the concentration-QT analysis is ‘negative’ (i.e., no effect on cardiac re-polarization) then a thorough QT/QTc study may not be needed at all. If the concentration-QT analysis is positive then a thorough QT/QTc study should be conducted; but, such a study would have been conducted regardless even if no concentration-QT analysis was conducted in the first place. The takeaway here is that if a concentration-QT (C-QT) analysis is conducted you could potentially eliminate the need to conduct a thorough QT/QTc (TQT) study later on. Regardless, it will always be beneficial to know the effect your drug has on cardiac re-polarization. Knowing this information sooner rather than later can also save time and costs during drug development.
Frequently Asked Questions
How much does a thorough QT/QTc study cost?
Cost is typically $2 Million to $4 Million. These studies usually enroll 40-60 patients or more.
How much does a concentration-QT (concentration-ECG) analysis cost?
Cost is typically $150,00 to $200,000. >10 fold savings compared to QTc/QT study.
Is an assessment of QT/QTc effects required for new drugs?
Yes. Either from thorough QT/QTc (TQT) study or by concentration-QT PK/PD analysis
What if the concentration-QT analysis is ‘negative’ (i.e., no effect on cardiac repolarization)?
The need for a TQT clinical study is likely not be needed.
What if the concentration-QT analysis is ‘positive’ (i.e., possible effect on cardiac repolarization)?
A TQT clinical study will be needed at a minimum but without the concentration-QT analysis the TQT study would have been done anyway.
What is the FDA’s opinion on concentration-QT?
Our experience is that the FDA has a favorable opinion of the Concentration-QT analysis. It may be a requirement for NCEs to have a concentration-QT analysis conducted. Allucent has direct experience with concentration-QT analysis supporting the position that a Thorough QT/QTc (TQT) study is not needed.
How can concentration-QT analysis support my exit strategy?
If you plan an exit (i.e., sale of the asset to large pharma, partnering with other companies, etc.) then the Concentration-QT analysis can provide a better negotiation position if the results are negative (i.e., no effect on cardiac repolarization). Then the drug has been “de-risked,” which means greater chance for approval and also less costs for the partner to conduct a thorough QT/QTc study.