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    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

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    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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    Torsades de Pointes

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    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

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    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

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    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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    Drug-Induced Torsades

    Primary: Drug effect (IKr

    block)

    Secondary: Effect Modifiers Bradycardia

    Hypokalemia

    Heart disease (LVH or CHF)

    Atrial fibrillation Female gender

    Form Fruste HERG mutation

    Metabolic inhibitors (pK); overdose

    Concomitant IKr blockers (pD)

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

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    KEY ECG Issues in New FDA-TDP

    Concept Paper November 2002

    All ECGs must be Recorded,Processed and StoredDigitally and using a central ECG laboratory ----- PaperECGs, 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 torule 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

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    Sources of QTc Variability

    ECG Measurement Method + Correction formulaof 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

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    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/RR0.5) 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 placebotreated and baseline QT and RR ECG data for adisease

    Recommended for ISS ECG Analysis Individual Based find exponent for each subject

    using at least 50-100 ECGs at baseline (pretreatment)

    Most accurate best considered for definitive Phase I ECG

    Trial

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    RR inter

    60080010001200141

    RegressionBazettFridericiaFDA

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    QTc Statistical Analysis

    1. Central Tendency: Mean Change (Timepoint to time point requires several ECGs at each point)

    2. Categorical analysislooking for outliers:

    A. maximum Mean change% change from baseline by:

    B. 30-60 and > 60 msec change

    C. % who have a new value > 500 msecD. % who have new abnormal U waves

    3. Dont expect to see arrhythmias - symptoms

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    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

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    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

    PopulationIntegrated Summary of Cardiac Safety Should

    Provide Most Robust Analysis


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