Dr. Paul Frohna, a biotech consultant with expertise in translational medicine and clinical pharmacology, presents an overview of the FDA's evolving perspectives on the QTc issue and the stand alone thorough QTc study.
Paul Frohna -PK-PD Modeling and the QT issue (part 1- fda perspective)
PK-PD Modeling with the QTc:Is it possible to avoid a TQT Study? Part 1. Understanding the FDA’s Perspective Paul A. Frohna, MD, PhD, PharmD Biotechnology Consultant Frohna Biotech Consulting www.frohnabiotechconsulting.com
Pharmacokinetics and Pharmacodynamics:Combining drug levels with biomarkers (DDQTc) Drug kin H CP keo CE Biomarker H Biomarker kout (DQTc) Response (TdP) Pharmacokinetics Pharmacodynamics This is an inexact science since not all drugs that cause an increase in QTc lead to Torsades de Pointe and sudden cardiac death, which is the real reason to care about QTc in drug development.
FDA View on Model-based DrugDevelopment and QTc Assessment“Model-based drug development is a priority for the CriticalPath Initiative. I believe it is the future of drugdevelopment”“We need to move from empirical evaluations to model-based, learn-confirm cycles to enhance the predictivecapacity of the drug development process” Janet Woodcock, M.D. Director, Center for Drug Evaluation and Research “Regulatory review of QT study is not complete without an assessment of concentration-QTc relationship” Norman Stockbridge, M.D., Ph.D. Director, Cardio-Renal Drug Products Head, Interdisciplinary Review Team for QT
Generating the Right QTc DataPackage for Your Drug
FDA Interdisciplinary Review Team (IRT) for QT Studies Provide standardization forum for study designs Quantitative Outcomes and Values – Concentration-Response required in all TQT studies – High rate of false positives when utilizing only dose- response data – CR is an important tool with additional statistical power to characterize QTc effects of a drug when you’re unable to conduct a TQT study • Anti-cancer compounds—too toxic for healthy subjects and at supratherapeutic doses, plus don’t want to use placebo in cancer patients
FDA Analysis of Sponsor’s TQT StudyData (Florian et al, JCP, 2011;51:1152-1162) FDA Hypothesis: A better understanding of how study design elements are likely to affect drug concentrations and the corresponding concentration–QTc relationship can be useful in designing future TQT studies. Objective: Determine what study design variables and patient covariates affect the Conc-QTc relationship of Moxi (positive control) Data: Several (20) TQT studies submitted to the FDA using Moxi with plasma concentration data and ΔΔQTcF Methods: Pooling and analyzing several (20) TQT studies to build pop PK model and conc-QTc model
ΔΔQTcF vs Time Plots for the 20Pooled TQT Studies by Sex and Race Sex: Male (dotted) and Female (solid) Race: Caucasian (solid), Black (dotted) and Asian (dot-dash)Florian et al., JCP, 2011;51:1152-1162
FDA’s Current Thinking… As more concentration-response QTc data are collected and submitted to the FDA, along with sophisticated PK-PD modeling, the FDA is mulling over the possibility that thorough QTc studies may not be required in the future. When is that future…not sure, but the future IS coming!