Evaluation of Cardiac Safety by ECG Findings: Focus on QTc Duration

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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 TherapyWhy?

• Increased risk of torsades de pointes
  (potentially fatal polymorphic ventricular
  tachycardia) as QTc interval increases - not all
  cases had QTc gt500 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 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

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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 gt30 per arm) for Power
• Population volunteers with half females
• Dose Ranging (gt 3-5X prefer gt10x) - ?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/RR0.33)
• 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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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 gt 60 msec change
C. who have a new value gt 500 msec D.
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)
• lt 5 msec - probably no concern
• 5 - 10 msec - increasing concern
• 10-20 msec - uncertain concern
• gt 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
  Population
• Integrated Summary of Cardiac Safety Should
  Provide Most Robust Analysis