Transcript Slide 1

BioQT and Pharmaceutical Development:
An Innovation in Cardiac Safety
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BioQT and Pharmaceutical Development:
An Innovation in Cardiac Safety
Welcome to a Live Web Conference
and Question & Answer Session
Jay W. Mason, MD
Industry Cardiac Safety Consultant
Chief Medical Officer
OBS Medical
Its Use in
Pharmaceutical
Development
Overview
1. What does BioQT do?
2. How does BioQT work?
3. Has BioQT been validated?
4. Does FDA accept BioQT data?
5. When should BioQT be used?
6. How can Sponsors access BioQT?
7. How much does BioQT cost?
What Does BioQT Do?
A Software Product
• Locates onset and offset of ECG waves
• (P, QRS, T)
• Accurately measures and annotates the QT,
PR, and QRS intervals
• Measures the RR interval to correct the QT
interval for heart rate
• Analyzes T-wave morphology and
reports change
What Does BioQT Do?
Automation and Data Sources
• Fully automated results with no human
involvement
• Semi-automated results with expert
over-reading
• Accepts
•
•
•
•
Standard 10-second ECGs
FDA (and other) XML data
Holter ECG data
Telemetry (eg, Surveyor) data
How Does BioQT Work?
A Probabilistic Model of the ECG
• BioQT is trained with cardiologist-read ECGs
• Mimics cardiologist P-onset, Q-onset, J-offset,
and T-offset annotations
• Estimates the accuracy (“confidence”) of
annotations on each beat by comparing the
waveform to those in the training set
• Tracks T-wave morphology by principal
components analysis
How Does BioQT Work?
ECG Expert Over-Reading
• Identifies beats with low confidence values
• For QT, PR, and QRS intervals
• Cardiologist reviews and adjusts annotations
• Cardiologist reading replaces the
automated reading
• High-confidence beats are not reviewed
• Greatly reduces the number of waveforms
requiring review
How Does BioQT Work?
ECG Expert Over-Reading
BioQT ECG Viewer
Analysis Server
Remote Cardiologist
How Does BioQT Work?
Holter Expert Over-Reading
• Analyzes the entire Holter data stream and
eliminates bad data
• Identifies common morphologies and assigns each
beat to one family or template
• Displays the templates, with automated
annotations, for cardiologist review
• Cardiologist selects templates that
need adjustment
• Applies template annotations to all beats of the
family via dynamic time warping
How Does BioQT Work?
Holter Expert Over-Reading
BioQT HM Viewer – Multi-template View
Remote
Cardiologist
Analysis Server
Remote
Cardiologist
BioQT HM Viewer – Single Template View
How Does BioQT Work?
Multi-Template View
How Does BioQT Work?
Single-Template View
Morphology Tracking
Sotalol 160 mg
Placebo
Morphology Tracking
Sotalol Mean Morphology change over 8 hours = +0.75
Moxifloxacin Mean Morphology change over 8 hours = - 0.012
Has BioQT Been Validated?
QT Measurement Validation Data Sets
Project
Data
BioQT Analysis
Manual Analysis
Training set
• 382 subjects
• 12,000 ECGs
Automated results
• 3,820 time points
• 10 time points/day
• 3 QT per time point
Sotalol
• 39 subjects
• 865 ECGs
Automated results
• 1,600 time points
• 16 time points/day
• 1 QTcF per time point
OBSB1005
• 72 subjects
• 144 Holters (24-hr)
Automated results
• 1,152 time points
• 8 time points/day
• 5 QTcF per time point
OBSB1006
• 99 subjects
• 10,881 ECGs (10-s)
Automated results
• 10,881 ECGs
• 12 time points/day
OBSB1007
• 21 subjects
• 144 Holters (24-hr)
Automated results
Refined (semi-automated) results
T-wave morphology results
• 200 time points
• 5 time points/day
• 3-5 QTcF per time point
OBSB1008
• 22 subjects
• 88 Holters (24-hr)
Automated results
Refined (semi-automated) results
• 704 time points
• 8 time points/day
• 3 QTcF per time point
Has BioQT Been Validated?
QRS Measurement Validation Data Sets
Project
Data
BioQT Analysis
Manual Analysis
OBSB1005
• 72 subjects
• 144 Holters (24-hr)
Automated results
•1,152 time points
• 8 time points/day
• 5 QRS per time point
OBSB1008
• 22 subjects
• 88 Holters (24-hr)
Automated results
Refined (semi-automated) results
• 704 time points
• 8 time points/day
• 3 QRS per time point
Has BioQT Been Validated?
QTc Point Estimates Show Good Correlation
Four Recent Pharma Studies: 204 subjects, 10,881 ECGs, 376 Holters
OBSB1005
OBSB1006
R2 = 0.92
R2 = 0.82
OBSB1007
OBSB1008
R2 = 0.93
R2 = 0.87
Has BioQT Been Validated?
Time Trends of QTc Point Estimates
Four Recent Pharma Studies: 204 subjects, 10,881 ECGs, 376 Holters
Has BioQT Been Validated?
QTc Point Estimate Outlier Trends
Sotalol Study: 39 Subjects, 865 ECGs
Has BioQT Been Validated?
Intra-Subject/Intra-Time Point QTc SD Showed
Lower QTc Variability
OBSB1005
OBSB1007
Manual SD mean = 8.34ms
BioQT SD mean = 7.79ms
BioQT lower by 7%
Manual SD mean = 8.31ms
BioQT SD mean = 5.26ms
BioQT lower by 37%
OBSB1008
Manual SD
BioQT SD
Manual SD mean = 7.1ms
BioQT SD mean = 4.9ms
BioQT lower by 31%
Has BioQT Been Validated?
Moxifloxacin Study Showed Improved
Prediction of Rx Status
OBSB1005: Crossover design, 72 subjects received moxifloxacin,
Correct Classification %
Examination of ddQTcF vs. time plots
Demographic-, Disease-, and ReaderSpecific Training and Templating
• HMM can be trained specifically for
• Age (especially pediatric)
• Disease state
• Specific readers
• Holter template libraries can be maintained and
updated for
• Age
• Disease state
• Specific readers
Does FDA Accept BioQT?
• Norman Stockbridge, MD, PhD
• Director, Division of Cardiovascular and Renal Products,
Office of Drug Evaluation I, Office of New Drugs, CDER, FDA
• Chairperson of the “Automated ECG Analysis” session at the
2009 DIA Cardiovascular Safety, QT and Arrhythmia in Drug
Development Conference
• When a control group is included in a study “the FDA will
make decisions using automated QT measurements if the
control results are as expected”
• At a meeting in October 2009, he expressed consternation at
the low level of use of automated technologies by pharma
• The FDA has received and reviewed prospective BioQT data
from a Sponsor to support a new drug application
• The FDA has received automated data as standalone in a
TQT study
Does FDA Accept BioQT?
Case Study
• Large pharmaceutical company found
unexpected QT prolongation in early Phase 1
study of a new drug
• The new drug is a nearly unique treatment for a
common disease
• QTc increased by 10–15 msec
• BioQT used to demonstrate that
• QT increase had reached steady state
• QT increase was not accompanied by
T-wave changes
Does FDA Accept BioQT?
Case Study (cont.)
• The Sponsor submitted
• BioQT data from baseline and all treatment days
• Standard ECG data from baseline and the final
treatment day
• Sponsor requested a waiver of the TQTS
requirement and approval to proceed to Phase 3
• FDA granted the waiver request and approved the
phase 3 study plan without additional demands
When Should BioQT Be Used?
TQT Studies
• BioQT as primary dataset
• Data collection as usual (continuous or by time point)
• Only BioQT analysis performed
• BioQT data alone submitted, if active control “behaves”
• Standard ECG analysis as primary dataset
• Standard ECG analysis performed and submitted
• BioQT analysis performed and submitted only if needed
• Missing ECG data
• Failed active control
• Unexpected QTc prolongation
• Both analyses performed and submitted
• Delay avoided
• Sponsor (and FDA) gain experience with BioQT
When Should BioQT Be Used?
Early Signal Detection
• Early dose escalation studies afford highest
exposures that will ever occur
• Early awareness of unexpected QT problem
• Powerful technique for internal decision making
• More expensive ECG or TQT study avoided
When Should BioQT Be Used?
Special Populations
• Oncology drug
• When studies in NHVs not possible
• Larger dataset provides usable data during
clinical instability
• Nausea and vomiting
• Hemodynamic changes
• Pain, fidgeting
• Larger dataset provides a more convincing alternative
to TQTS
• Other drugs prohibited in NHVs
• Alternative to TQTS
• More extensive data to balance limited subject numbers
• Drugs used in actively unstable patients
• Poorly tolerated drugs
When Should BioQT Be Used?
Future Use
• Automated methods will soon replace the
standard ECG for measurement of QTc
• Pharma companies should gain experience with
them now
• Automated methods will be used for
measurement of the other ECG intervals
• Reliable strategies for automated diagnostic
analysis will emerge
• T-wave morphology and other new repolarization
analyses will supplant the QT measurement
How Can Sponsors Access BioQT?
OBS Medical
• Sponsor can provide datasets (in appropriate
format) to OBS for analysis
• Retrospective analysis
• Data collected at a phase 1 or other clinical unit
• Data collected by a core ECG lab
• OBS can provide physician over-reading services
• OBS can install BioQT at a pharma company
• Not currently supporting ECG or Holter
collection logistics
• Not currently providing comprehensive
project management
How Can Sponsors Access BioQT?
Phase 1 CRUs
• BioQT is installed at Spaulding Clinical
(West Bend, Wisconsin)
• BioQT may be installed in other CRUs
• Local installation has advantages
• Eliminates the need for data transfers
• Speeds availability of data
• Near real-time reporting of QT and
morphology data
• Reduces cost
• The CRU can deliver data to OBS for analysis if
it does not have a BioQT installation
How Can Sponsors Access BioQT?
Core ECG Labs
• OBS has initiated conversations with ECG core
labs that will allow them to manage the process
and deliver BioQT data to the Sponsor
• This can be achieved with or without a local
installation at the core lab
• OBS hopes to involve many core labs as
partners in providing BioQT to Sponsors
Price Categories
Methodology
• ECG analysis
• Automated
• Semi-automated
• Holter analysis
• Automated
• Semi-automated (Refined)
• T-wave morphology
Use
• In addition to standard
ECG analysis
• In lieu of standard ECG
analysis
• Stand alone
• Standard ECG as back up
• With/without T-wave
analysis
• With/without on-site
installation
Sponsor/CRO Cost
Savings Opportunities
• Increased workflow efficiency
• Faster completion of analysis and reporting
• More accurate data analysis
• Less cost to execute analysis
Summary
• Automated/semi-automated method for QTc, PR,
and QRS measurement on large datasets
• Validated using multiple datasets
• FDA accepts BioQT data when an active control
is included in the study
• Utility in TQT studies and in other settings
• BioQT analysis can be obtained from
• OBS Medical
• Phase 1 units
• Core ECG laboratories
OBS Medical Contact Information
Dr. Benhur Aysin
317-581-9236
OBS Medical
Two Meridian Plaza
10401 N Meridian Street
Suite 300
Indianapolis, IN 46290
BioQT and Pharmaceutical Development:
An Innovation in Cardiac Safety
Question & Answer Session
BioQT and Pharmaceutical Development:
An Innovation in Cardiac Safety
Thank You for Your Participation