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

3. Torsades de Pointes

4. Drugs Discontinued from Marketing in Last Decade Due to QTc Effect TerodilineGU TerfenadineAntihistamine AstemizoleAntihistamine SertindoleCNS GrepafloxacinAntibiotic DroperidolCNS CisaprideGI

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

7. Drug-Induced Torsades u Primary: Drug effect (I K r block) u Secondary: Effect Modifiers u Bradycardia u Hypokalemia u Heart disease (LVH or CHF) u Atrial fibrillation u Female gender u Form Fruste HERG mutation u Metabolic inhibitors (pK); overdose u Concomitant IKr blockers (pD)

8. What is the QT Interval? All other ECG Changes also Important

9. KEY ECG Issues in New FDA-TDP Concept Paper November 2002 All ECGs must be Recorded,Processed and Stored Digitally and using a central ECG laboratory -----Paper ECGs, if needed, can be digitized Analysis should be Manual (digipad or on screen) – Automated for “safety analysis” ? An Intense or Thorough Phase I ECG Trial is required to rule out a 5 msec effect for all Bioactive Agents (important design features: negative and positive control and dose effect of new agent), and, Digital Annotated ECG waveform raw data to be provided for critical ECG data using the XML.DTD

10. Sources of QTc Variability ECG Measurement Method + Correction formula of QT to QTc Frequency of ECGs Baseline and on Therapy ECGs (cover exposure, diurnal) Sample Size (need >30 per arm) for Power Population: volunteers with half females Dose Ranging (> 3-5X prefer >10x) - ?need to study metabolic inhibitors Control Groups: negative and positive

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

13. QTc Statistical Analysis 1. Central Tendency: Mean Change (Time point to time point requires several ECGs at each point) 2. Categorical analysis looking for outliers: A. maximum Mean change % change from baseline by: B. 30-60 and > 60 msec change C. % who have a new value > 500 msec D. % who have new abnormal U waves 3. Don’t expect to see arrhythmias - symptoms

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