Study results support replacing the expensive and time-consuming TQT study with QT assessment in early clinical development
PRINCETON, NJ – Dec. 23, 2014 – Certara®, the leading global technology-enabled drug development and drug safety consultancy, today announced that its Vice President and Lead Scientist Christine Garnett, PharmD, was session chair at the Dec.12 Cardiac Safety Research Consortium (CSRC) meeting at the U.S. Food and Drug Administration (FDA) campus in Silver Spring, MD where the results from the Prospective IQ-CSRC Clinical Study were presented.
“This study indicated that using model-based approaches during routine early clinical research has the potential to shift the current paradigm for QT assessment,” said Dr. Garnett. “Results showed that exposure-response modeling of Phase 1 clinical data could be used to waive the Thorough QT/QTc (TQT) study for most drugs.”
The ICH E14 guidance recommend that all new drugs with systemic bioavailability are assessed for the ability to delay cardiac repolarization as measured by the QT/QTc interval on the surface electrocardiogram (ECG). For most drugs, this evaluation is performed in the Thorough QT/QTc (TQT) study.
In first-in-man single-ascending dose (SAD) studies, like the Prospective IQ-CSRC Clinical study, small cohorts of healthy volunteers receive escalating doses of the new chemical entity often up to the maximally-tolerated dose. Sponsors often use high quality ECG monitoring in these studies to gain an early understanding of a drug’s potential cardiotoxicity. The study’s authors leveraged model-based approaches gained from using ER analysis of data from TQT studies and from trials in patients to optimize the study design.
In the Prospective IQ-CSRC Clinical study, healthy subjects received either drugs with well-characterized QT prolongation effects or placebo. The drug doses were selected by the FDA to obtain QTc prolongation of 10-12 ms, which is around the regulatory threshold. ECG recording processing and analysis was performed using the same approach as in TQT studies. A linear mixed-effects ER model was used to analyze the data pooled across all dose levels which increases the precision of the estimated QTc effect. Model-based criteria were used to determine if the resulting drug effect detected QTc prolongation of around 10 ms.
The study was successful with the “QT positive” drugs showing characteristic QT prolongation while the “QT negative” drug did not. The results of the study were published in Clinical Pharmacology and Therapeutics.
This study provides evidence that intense ECG assessment in a SAD study paired with ER analysis can detect QTc prolongation and provides a pathway to waive the TQT study.
Certara is the leading global technology-enabled drug development and drug safety consultancy. Its customers include hundreds of biopharmaceutical companies around the globe, together with several regulatory agencies. Certara’s solutions, which span the discovery, preclinical and clinical stages of drug development, enable data-driven decisions, leading to more precisely designed trials with a reduced risk of failure and improved subject safety.
For more information, visit www.certara.com.
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