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TUESDAY, MAY 13

7:30am Continental Breakfast Breakout Discussions 

8:30 Chairperson’s Remarks 
William Wheeler, M.D., FACC, Global Medical Director, Centralized Cardiac Safety Services, 
MDS Pharma Services

8:40 Regulatory, Procedural, and Statistical Considerations in the Thorough QT Study: The Complexity of the Design of a Thorough QT Study
Charles M. Beasley, Jr., M.D., FFPM, Chief Scientific Officer, Global Product Safety, Eli Lilly & Co.
The QTc shows considerable variability due both to difficulties in precise measurement and intrinsic variability. TQTS design features MIGHT reduce variability and improve the precision of the difference between treatments. This talk will discuss: 1) homogeneous vs. diverse subjects; 2) parallel vs. cross-over design; 3) number of replicate ECGs averaged; 4) correcting QT for heart rate; 5) positive control; 6) blinding; 7) can adequate exposure to drug be achieved with a single dose; 8) what value is compared between treatments; 9) time points of data acquisition; 10) protecting against inflated potential for false finding inherent in multiple time point comparisons; 11) inclusion of pK assessments.

9:10 Select Debatable Issues around QTc Assessment in Clinical Trials
Nenad Sarapa M.D., M.Sc., Senior Director, Experimental Medicine, Johnson & Johnson Pharmaceutical Research & Development
Three years after the adoption of the ICH E14 guidance, the structured clinical QTc assessment has become the integral component of drug development. While requiring a measurement-intensive thorough QTc study (TQTS) for all non-antiarrhythmic drugs with systemic availability, the E14 guidance was deliberately non-prescriptive in order to allow different approaches. As global experience with TQTS has built up, the need has emerged for more clarity about design elements, study conduct and statistical analysis. This presentation will describe the speaker’s perspective on the sponsor’s and regulatory approaches to select issues with the design, conduct and analysis of TQTS (e.g. blinded moxifloxacin as positive control, criteria for adequate sensitivity of TQTS assay, conduct of TQTS with 3 or 2 treatment arms, comparisons of QT interval measurement methods, inter- and intra-reader variability, ECG warehousing). 

9:40 Redesign of QT Studies for Efficiency and Speed
Jay W. Mason, M.D., Cardiac Safety Consultant, Professor of Medicine, University of Utah.
Definitive QT studies (DQTS) compliant with the ICH E-14 Guidance recommendations are very costly and may delay market availability of new drugs. New approaches are needed to reduce the cost and decrease the time required for performance of these studies. Eliminating variability in QTc is an effective approach which can be achieved in a variety of novel ways. Statistically-based reduction in the number of recorded ECGs, the number of sampling time points and the number of recording days can half the cost and duration of a DQTS. 

10:10 Networking Coffee Break in the Exhibit Hall 

10:50 The Impact of Autonomic Tone on QT Prolongation Assessment-Translation of Pre-Clinical Data to Clinical Outcomes
Anthony Fossa, Ph.D., Research Fellow, Translational and Molecular Medicine, Pfizer Global Research & Development
The beat-to-beat dynamicity of the QT-RR interval relationship is difficult to assess with the use of traditional correction factors (QTc). Using sequential beat-to-beat analyses of the temporal heterogeneity developed in conscious dogs, this work can now be performed in humans using Holter-based techniques developed to differentiate and quantify autonomic changes from impaired repolarization. Translation of this technique to human data will be demonstrated with real life examples of development issues where autonomic tone can impact the interpretation of results. Using traditional methods, are we really making proper decisions or are we hurting our industry/companies by not using more comprehensive physiological assessments?

11:20 Proarrhythmic Cardiac Safety: Assessment Methodologies and Benefit-Risk Assessments
J. Rick Turner, Ph.D., PGCE, Chairman, Department of Clinical Research and Director, Cardiac Safety Education Center, Campbell University School of Pharmacy, North Carolina
While QT/QTc interval prolongation remains a focus of regulatory guidance on torsadogenic liability assessment, other biomarkers may be found to provide complementary and/or more predictive information. This presentation examines assessment methodologies for such markers, including transmural dispersion of repolarization and T-wave alternans. The associated benefit-risk assessments are also discussed.

11:50 Q&A with Audience

12:20pm Close of Cardiotoxicity and Drug Safety Conference

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