Since 2005 the US Food and Drug Administration (FDA) has required the evaluation of a new molecular entity in a thorough QT (TQT) study, which is intended to determine a drug’s effect on the QT interval. The QT interval represents the duration of ventricular depolarization and subsequent cardiac repolarization, measured from the beginning of the QRS complex to the end of the T wave. An understanding of the drug’s effects on QT as well as cardiovascular adverse events are mandated by the guidance. The design, conduct, analysis, and interpretation of clinical TQT studies are covered in the FDA Guidance for Industry, E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs1. In general, the study design is a placebo-control treatment of a drug at two dose levels, therapeutic and supratherapeutic dose, and an unblinded positive control usually in a cross-over or parallel design. The recommended metric to analyze is the time-matched mean difference between the drug and placebo baseline-adjusted over the collection period.
In recent years, the use of exposure response (ER) modeling of intensive electrocardiogram (ECG) captured in early phase I single ascending dose/multiple ascending dose (SAD/MAD) studies as a waiver to a TQT study has been discussed, endorsed and practiced2-4. This endorsement of ER modeling was incorporated into a guidance document in 2015 with the ICH5 and recently with the FDA in 20176. There are several advantages to the ER modeling approach.
- Incorporates QTc evaluation into early phase I SAD/MAD trial where a wide range of drug exposure is achieved as a single dose or at steady state, and often incorporating evaluation of potential food effects.
- ER modeling to evaluate QTc is consistent with ER modeling to evaluate drug-drug interactions, efficacy, safety, intrinsic and extrinsic factors that can impact exposure, evaluating new formulations, etc.
- Allows for data to be analyzed across multiple cohorts and multiple studies (assuming the ECG collected is of high quality alongside pharmacokinetic sample). This approach would estimate the relationship between the exposure of a drug and its effect on QTc over a wide range of concentrations (as opposed to the two dose levels in a TQT) and takes advantage of all the data collected rather than restricting the evaluation to a specific time point at a specified dose.
- Eliminates the need for moxifloxacin, the positive control required for assay sensitivity in a TQT study if there are robust and high-quality ECG data characterizing the response at sufficiently high multiple of the clinically relevant exposure.
- Attains information regarding the potential liability on QTc early during Phase I clinical studies will provide a more efficient and effective assessment of a drug developability and brings critical benefits to patient’s safety through appropriate measures to address such liability if present. In contrast, TQT assessment is commonly conducted at late stage clinical development.
- Incorporates high-quality ECG evaluation in phase I SAD/MAD studies is more economical than the cost of conducting a stand-alone TQT.
Since the endorsement of regulatory agencies on the ER model as an option to TQT evaluation, there have been several studies submitted to the Agency using this approach. Some are successful, some not. The key basis for the unsuccessful studies using ER model was determined to be primarily due to an inadequate prespecified modeling, design, and analysis plan of the study protocol7. Interaction with the FDA’s Interdisciplinary Review Team for guidance and support for the conduct of a QT study in early clinical development is highly recommended for greater chance of a successful filing.
Alex Vo, Ph.D.
Aclairo Pharmaceutical Development Group, Inc.
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- FDA Guidance for Industry. E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs 2005
- Garnett CE, Beasley N, Bhattaram VA, Jadhav PR, Madabushi R, Stockbridge N, Tornoe CW, Wang Y, Zhu H, Gobburu JV. Concentration-QT relationships play a key role in the evaluation of proarrhythmic risk during regulatory review. J Clin Pharmacol 2008 48(1):13-8
- Darpo B, Sarapa N, Garnett C, Benson C, Dota C, Ferber G, Jarugula V, Johannesen L, Keirns J, Krudys K, Ortemann-Renon C, Riley S, Rogers-Subramaniam D, Stockbridge N. The IQ-CSRC prospective clinical phase 1 study: “Can early QT assessment using exposure-response analysis replace the thorough QT study?”. Ann Noninvasive Electrocardiol 2014 19(1):70-71
- Darpo B, Benson C, Dota C, Ferber G, Garnett C, Green CL, Jarugula V, Johannesen L, Keirns J, Krudys K, Liu J, Ortemann-Renon C, Riley S, Sarapa N, Smith B, Stoltz RR, Rogers-Subramaniam D, Stockbridge N. Results from the IQ-CSRC prospective study support replacement of the thorough QT study by QT assessment in the early clinical phase. J Clin Pharmacol 2015 97(4):326-35
- ICH E14 Guideline: The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs – Questions & Answers (R3) 2015
- FDA Guidance for Industry. E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs – Questions and Answers (R3) 2017
- Grenier J, Paglialunga S, Morimoto B, Lester R. Evaluating cardiac risk: exposure response analysis in early clinical drug development. Drug, Healthc Patient Saf 2018 10:27-36