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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