1	Evaluation of Cardiac Safety by ECG Findings: Focus on QTc Duration Joel Morganroth, M.D. Clinical Professor of Medicine University of Pennsylvania Chief Scientist, eResearchTechnology
2	Prolongation of the QTc Interval: Cardiac Safety Issue of New Therapy Why? Increased risk of torsades de pointes (potentially fatal polymorphic ventricular tachycardia) as QTc interval increases - not all cases had QTc >500 msec
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4	Drugs Discontinued from Marketing in Last Decade Due to QTc Effect Terodiline GU Terfenadine Antihistamine Astemizole Antihistamine Sertindole CNS Grepafloxacin Antibiotic Droperidol CNS Cisapride GI
5	Terfenadine Mean change in QTc at clinical dose: 6 msec (retrospectively detected by digital manual ECG analysis after marketing) Mean change in QTc at Tmax (Mean max change) - 18 msec Max change in the presence of a metabolic inhibitor (ketoconazole) – 50-100 msec Benefit: reduce minimal symptoms Risk: death Result: Removed from the Market
6	Other Drugs That Prolong the QTc Interval (some examples ONLY) CNS: ziprasadone, thioridazine, risperidone Antibiotics: clarithromycin, ketoconazole, fluconazole, moxifloxacin Neoplastic Agents: arsenic, tamoxifen Anti-rejection: tacrolimus Class I and III Antiarrhythmic Agents: quinidine, sotalol, amiodarone
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8	What is the QT Interval? All other ECG Changes also Important
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11	Corrected QT Interval - QTc QTc is the QT corrected for heart rate (QT decreases as the heart rate increases) How to correct is the subject of FDA-TPD guidance: Bazett formula (QT/RR^0.5) Undercorrects at low heart rates-most limitations Fridericia formula (QT/RR^0.33) Least limitations of the fixed exponent correction Population Based – find exponent for placebo treated and baseline QT and RR ECG data for a “disease” Recommended for ISS ECG Analysis Individual Based – find exponent for each subject using at least 50-100 ECGs at baseline (pre treatment) Most accurate – best considered for definitive Phase I ECG Trial
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14	Continuous Interval Analysis Regulatory Signals Mean Change* of QTc Duration (Degree of outliers equally important) < 5 msec - probably no concern 5 - 10 msec - increasing concern 10-20 msec - uncertain concern > 20 msec - definite concern BUT DEPENDS ON RISK-BENEFIT OF THERAPY
15	Overall Cardiac Safety Determination of a New Agent Preclinical Data provides Clues but Trumped by Adequate Clinical Data Thorough Phase I ECG Trial Now Recommended to Judge Intensity of ECGs in Phase II and III Phase II and III ECG Data in the Target Population Integrated Summary of Cardiac Safety Should Provide Most Robust Analysis