BioQT and Pharmaceutical Development: An Innovation in Cardiac Safety

1. BioQT and Pharmaceutical Development: An Innovation in Cardiac Safety The Web Conference Will Begin Shortly To join the audio portion of the meeting please call Toll-free number (US/Canada): 866-699-3239 Toll-free number (Sweden): 020-79-4035 Access code: 577 135 280

2. BioQT and Pharmaceutical Development: An Innovation in Cardiac Safety Welcome to a Live Web Conference and Question & Answer Session

3. Jay W. Mason, MD Industry Cardiac Safety Consultant Chief Medical Officer OBS Medical

4. Its Use in Pharmaceutical Development

5. Overview • What does BioQT do? • How does BioQT work? • Has BioQT been validated? • Does FDA accept BioQT data? • When should BioQT be used? • How can Sponsors access BioQT? • How much does BioQT cost?

6. 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

7. 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

8. 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

9. 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

10. How Does BioQT Work?ECG Expert Over-Reading Analysis Server BioQT ECG Viewer Remote Cardiologist

11. 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

12. How Does BioQT Work?Holter Expert Over-Reading Analysis Server BioQT HM Viewer – Multi-template View BioQT HM Viewer – Single Template View Remote Cardiologist Remote Cardiologist

13. How Does BioQT Work?Multi-Template View

14. How Does BioQT Work?Single-Template View

15. Morphology Tracking Sotalol 160 mg Placebo

16. Morphology Tracking Sotalol Mean Morphology change over 8 hours = +0.75 Moxifloxacin Mean Morphology change over 8 hours = - 0.012

17. Has BioQT Been Validated?QT Measurement Validation Data Sets

18. Has BioQT Been Validated?QRS Measurement Validation Data Sets

19. 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

20. Has BioQT Been Validated?Time Trends of QTc Point Estimates Four Recent Pharma Studies: 204 subjects, 10,881 ECGs, 376 Holters

21. Has BioQT Been Validated?QTc Point Estimate Outlier Trends Sotalol Study: 39 Subjects, 865 ECGs

22. Has BioQT Been Validated?Intra-Subject/Intra-Time Point QTc SD ShowedLower QTc Variability OBSB1005 OBSB1008 OBSB1007 Manual SD BioQT SD 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% Manual SD mean = 7.1ms BioQT SD mean = 4.9ms BioQT lower by 31%

23. Has BioQT Been Validated?Moxifloxacin Study Showed Improved Prediction of Rx Status OBSB1005: Crossover design, 72 subjects received moxifloxacin, Examination of ddQTcF vs. time plots Correct Classification %

24. Demographic-, Disease-, and Reader-Specific 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

25. 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

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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

35. Price Categories Methodology 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 • ECG analysis • Automated • Semi-automated • Holter analysis • Automated • Semi-automated (Refined) • T-wave morphology

36. Sponsor/CRO Cost Savings Opportunities • Increased workflow efficiency • Faster completion of analysis and reporting
 • More accurate data analysis • Less cost to execute analysis

37. 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

38. OBS Medical Contact Information OBS Medical Two Meridian Plaza 10401 N Meridian Street Suite 300 Indianapolis, IN 46290 Dr. BenhurAysin317-581-9236

39. BioQT and Pharmaceutical Development: An Innovation in Cardiac Safety Question & Answer Session

40. BioQT and Pharmaceutical Development: An Innovation in Cardiac Safety Thank You for Your Participation