3950s1 02 fda-morganroth
TRANSCRIPT
-
7/30/2019 3950s1 02 FDA-morganroth
1/15
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
-
7/30/2019 3950s1 02 FDA-morganroth
2/15
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
-
7/30/2019 3950s1 02 FDA-morganroth
3/15
Torsades de Pointes
-
7/30/2019 3950s1 02 FDA-morganroth
4/15
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
-
7/30/2019 3950s1 02 FDA-morganroth
5/15
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
-
7/30/2019 3950s1 02 FDA-morganroth
6/15
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
-
7/30/2019 3950s1 02 FDA-morganroth
7/15
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)
-
7/30/2019 3950s1 02 FDA-morganroth
8/15
What is the QT Interval?All other ECG Changes also Important
-
7/30/2019 3950s1 02 FDA-morganroth
9/15
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
-
7/30/2019 3950s1 02 FDA-morganroth
10/15
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
-
7/30/2019 3950s1 02 FDA-morganroth
11/15
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
-
7/30/2019 3950s1 02 FDA-morganroth
12/15
RR inter
60080010001200141
RegressionBazettFridericiaFDA
-
7/30/2019 3950s1 02 FDA-morganroth
13/15
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
-
7/30/2019 3950s1 02 FDA-morganroth
14/15
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
-
7/30/2019 3950s1 02 FDA-morganroth
15/15
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
PopulationIntegrated Summary of Cardiac Safety Should
Provide Most Robust Analysis