Dr. Jay Mason, Chief Medical Officer, Spaulding Clinical Research presents on Cardiac Surveillance Strategies to Improve Safety and Avoiding the Thorough QT Study
3. Outline
• The basis for and history of the ICH E-14 Guidance
• Current status of the Guidance
– Q&A issued by ICH, FDA, Health Canada
– Additional clarifications in FDA response letters
– Changes and updates in a nutshell
• What could be improved?
– Timing
– Moxifloxacin exposure
– More informative endpoints
– Cost
• Alternative strategies
– Front load and taper
– Eliminate the active control arm
– Add better endpoints: T-wave quantification
– Control cost
• Automation
• Purpose-built device and analysis
4.
5. E-14 Requirements: Thorough QT Study
• Applies to almost all new drugs (>95%)
• Detect 5 msec (UCB 10 msec) change in QTc
• Between 4,000 and 30,000 ECGs per study
• Centralized ECG interpretation
• Placebo control
• Active control (moxifloxacin)
• Supratherapeutic dose (4X – 10X)
• Performed prior to approval, usually after Phase 2
• Annotated XML file
6. Additions and Clarifications
• Thorough analysis of heart rate, PR and QRS should be
included
• Clinical dose arm not required
• Blinding of moxifloxacin not required
• Automation is acceptable when a positive control is
included
• Zhang/Machado sample size recommendations
• Bazett QT correction no longer required
• Multiple endpoint adjustment to control type I error
required for the assay sensitivity test
• Account for possible delayed effect
• Perform PK-PD modeling
7. What could be improved?: Timing
Phase 1 Phase 2 Phase 3 Phase 4
ECG Quality
ECG Quantity
ECG Information
Two Problems with this timing
One
• ECG quality, quantity and resulting information
are lowest in Phase 1
• Ironically, the highest doses and most careful
exploration of pharmacokinetics occur in Phase 1
• A huge opportunity lost
Two
• Subjects are exposed to the drug in Phases 1 and
2 at supratherapeutic doses
• Often several hundred subjects and patients are
exposed in Phases 1 and 2
• Aren’t they entitled to the same protection the
TQTS is designed to guarantee in Phase 3?
8. Alternative Timing Strategy
Strategy
• Front load ECG acquisition
• Centralize and maintain high quality
throughout the program
• Reduce frequency of time points and
replicates as newly gained information
warrants
Results
• High quality ECG information gathered
at maximum dosage
• Early warning of QT and other ECG
issues
• Subject/patient safety improved
• Early out
• TQTS avoided
• Cost reduced?
Phase 1 Phase 2 Phase 3 Phase 4
9. What could be improved?: Moxifloxacin Exposure
Moxifloxacin is not totally benign
– QT prolongation and torsades de pointes
– Hypersensitivity reaction (SJS, TEN)
– C. difficile (CDAD)
– Tendon rupture, etc.
Alternative Moxifloxacin strategies
– High quantity and quality of ECGs reduce need for active control
– Methods and investigative sites that accurately measure QTc change are now
well known
– Maintenance of high quality in Phase 3 (and 4) reduces chance of missed
repolarization liability
– Other sound methods for demonstrating assay sensitivity have been proposed
• Positional changes in QTc
• Statistical methods to discern QTc precision
10. What could be improved?: Endpoints
• QTc prolongation has extremely low specificity for torsades de pointes
• T-wave change has higher specificity and sensitivity in animal models
• T-waves are currently assessed subjectively without quantification
• T-wave segmentation (e.g., Tpeak – Tend)
• Serial quantification of eigenvectors (e.g., BioQT)
Alternative strategy: Quantify T-wave
13. Alternative Cost Strategy: Automation
• Faster
• Less expensive
• Human error eliminated
• Variability decreased
• Sample size decreased
• The impossible made possible
– Well-founded QTcI
– T-wave morphology tracking
– Other analyses requiring large quantities or
continuous data.
15. • Reduce the cost of manufacturing and leasing the
electrocardiograph
• Reduce the cost of shipping the device
• Simplify ECG acquisition to reduce training costs
• Eliminate the cost of human error
• Enhance data quantity, quality and reliability
Alternative Cost Strategy: Purpose-
built devices
17. TQT Alternative Strategy
• Front-load and taper ECG acquisition to get
earlier repolarization answer
• Eliminate the active control arm for patient
safety and cost reduction
• Monitor T-wave morphology for better
assessment of risk
• Automate ECG analysis to reduce cost
• Use more cost effective devices and analyses
18. • Implement a sufficiently simple, inexpensive, reliable ECG
process to allow high-quality ECG collection from FIM to
pivotal phase 3 trials and beyond.
• Continuously update ECG safety prediction.
• Adjust safety monitoring requirements in accordance
with prediction.
• Carry requirements into phase 4 if necessary.
• No TQT!
• “Thorough ECG Strategy”
Thorough ECG Strategy