1. QT and arrhythmia issues in drug development. DIA Washington DC, April 2008 Borje Darpo MD PhD Unresolved procedural, regulatory and statistical issues in assessing human QT prolongation and performing the ‘thorough QT study’ Borje Darpo MD PhD, FESC Associate Professor in Cardiology Pharmaceutical Consultant borje.darpo@telia.com

2. QT and arrhythmia issues in drug development. DIA Washington DC, April 2008 Borje Darpo MD PhD Objective of presentation To outline some areas within clinical QT assessment, which I believe need more studies and publicly shared data to allow for definitive recommendations ‘More than one road lead to Rome – until someone builds a motorway’ Hieronymus ‘Filibuster’ Hippocampus A.D. -07

3. QT and arrhythmia issues in drug development. DIA Washington DC, April 2008 Borje Darpo MD PhD Some unresolved issues – not necessarily the most important ones Thorough QT study 1.Baseline assessment 2.Heart rate correction algorithm for drugs without or with a small inherent effect on the heart rate 3.The role of the positive control 4.Which effect of the positive control establishes assay sensitivity? 5.How should emerging new techniques be validated?

4. QT and arrhythmia issues in drug development. DIA Washington DC, April 2008 Borje Darpo MD PhD 1. Baseline in the TQT study Background: Adjustment for baseline measurements is important for reducing the influence of inter-subject differences and general, as well as study-specific, diurnal effects such as those due to food Currently ‘recommended’ (code for ‘recently requested by the FDA’s IRT’): Cross-over studies: Predose baseline immediately before dosing on treatment day in each period Parallel studies: One full, ‘time-matched’ baseline on the day before dosing in each treatment group

5. QT and arrhythmia issues in drug development. DIA Washington DC, April 2008 Borje Darpo MD PhD Baseline in parallel TQT studies 1.Pre-dose baseline: Immediately before dosing on Day 1 in each Tx group. 2.Time-matched baseline (‘recommended’): Recorded at same time-points on Day -1 as after dosing on Day 1. 3.Time-averaged: Recorded as above, but baseline derived from average of Day -1 values

6. QT and arrhythmia issues in drug development. DIA Washington DC, April 2008 Borje Darpo MD PhD Baseline in parallel TQT studies Study# subjects placebo /moxi Positive Control Collection days ECGs Replicates; time points (hours) 125/24Blinded moxi 400 mg qd for 5 days, -1 and 51x; 0, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 24 246/44Open label moxi 400 mg, single dose -1 and 13x; 0, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 347/48Blinded moxi 400 mg for 6 days -1 and 63x; 0, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 24 435/35Open label moxi 400 mg for 7 days -1 and 73x; 0, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 23 In manuscript Darpo, Ferber, Sarapa

7. QT and arrhythmia issues in drug development. DIA Washington DC, April 2008 Borje Darpo MD PhD Baseline adjusted, placebo corrected QTcF after 400 mg moxifloxacin for 7 days SD varied between 11 and 13 across baselines and Tx

8. QT and arrhythmia issues in drug development. DIA Washington DC, April 2008 Borje Darpo MD PhD Baseline assessment in parallel TQT studies Ratio between SD’s predose or averaged / time-matched Median SD values ranged from 8 to 17 across studies and Tx Conclusion: Variability consistently lower with averaged baseline compared to time-matched or predose

9. QT and arrhythmia issues in drug development. DIA Washington DC, April 2008 Borje Darpo MD PhD Baseline in parallel TQT studies Conclusions: ‘Averaged’ baseline reduced total variability more than time- matched, thus allowing for more efficient study designs If the subject-specific part of circadian variability was substantial, time-matched BL would have significantly reduced the total variability Our data suggest that the subject-specific circadian variability was relatively small and ‘averaging’ therefore resulted in an over-all lower variability

10. QT and arrhythmia issues in drug development. DIA Washington DC, April 2008 Borje Darpo MD PhD 2. Heart rate correction algorithm for drugs without an effect on the heart rate Full time-matched baseline is often advocated in cross-over studies to allow for individual heart rate correction (QTcI) often also recommended for drugs without effect on the heart rate ECGs are often recorded after 10-20 minutes of supine rest which generates relatively narrow heart rates recorded at rest This approachgenerates QTcI values, which rarely are different from QTcF for drugs without or with a small effect on the heart rate, but certainly requires more ECGs and 1 additional study day/Tx period for which the utility for drugs with an effect on the heart rate can be questioned (or at least warrants further studies). There is yet no general agreement on how to study the QTc effect with drugs with an inherent effect on the heart rate, through e.g. autonomic alteration

11. QT and arrhythmia issues in drug development. DIA Washington DC, April 2008 Borje Darpo MD PhD 3. Why are we using a positive control? According to ICH E14: “The confidence in the ability of the study to detect QT/QTc prolongation can be greatly enhanced by the use of a concurrent positive control group to establish assay sensitivity“ “…, the positive control (whether pharmacological or non- pharmacological) should be well-characterized and consistently produce an effect corresponding to the largest change in the QT/QTc interval that is currently viewed as clinically not important to detect (a mean change of around 5 ms or less)”

12. QT and arrhythmia issues in drug development. DIA Washington DC, April 2008 Borje Darpo MD PhD Establishing assay sensitivity Uncontroversial in X-over studies with short duration in which + control can be included as separate Tx period Challenging in studies with long duration of Tx or long wash-out (e.g. dose escalation, drug accumulation) Recently the IRT has requested running the positive control in separate Tx group in parallel TQT studies – which means that 67% of subjects are exposed to either placebo or one dose of moxifloxacin

13. QT and arrhythmia issues in drug development. DIA Washington DC, April 2008 Borje Darpo MD PhD IRT request for parallel-group studies Subjects 1 - 40 Baseline Day 21 Drug Subjects 41 - 80 Baseline Day 21 Placebo Subjects 81 - 120 Baseline Day 21 Separate + control Day of primary assessment 67%

14. QT and arrhythmia issues in drug development. DIA Washington DC, April 2008 Borje Darpo MD PhD Question: Does the gain with separate + control Tx-group justify the added cost and complexity of the study? Could an alternative approach be acceptable? All Tx periods are extended by 1 day and a single-dose of + control/placebo is added on this day Issue: Baseline adjustment and placebo-correction will be within group for + control effect but not for drug effect

15. QT and arrhythmia issues in drug development. DIA Washington DC, April 2008 Borje Darpo MD PhD Parallel-group studies Subjects 1 - 40 Baseline Day 21 Drug Subjects 41 - 80 Baseline Day 21 Placebo/+ control Day of primary assessment X Means 33% less subjects

16. QT and arrhythmia issues in drug development. DIA Washington DC, April 2008 Borje Darpo MD PhD 4. How does the + control establish assay sensitivity? 1.FDA IRT: The effect should be comparable to other similar studies using moxifloxacin and an effect > 5 ms should be demonstrated (lower CI > 5 ms). 2.Health Canada: The peak effect of the + control should be ‘around 5 ms’ and the lower bound of the CI above 0 ms 3.Others 1: There is no difference between a peak effect and an effect at other time-points. An statistically significant effect ‘around’ 5 ms at any time point is therefore sufficient 4.Others 2: The precision of the effect should allow detection as small as 5 ms, i.e. the width of the CI should be < + 5 ms.

17. QT and arrhythmia issues in drug development. DIA Washington DC, April 2008 Borje Darpo MD PhD Study Drug-free NAutoManual/CADifference 11846374 + 25.7394 + 25.5-20 + 10.6 2531380 + 26.9399 + 28.9-19 + 9.1 32610404 + 32.3391 + 28.213 + 16.2 42803391+ 26.9377 + 27.114 + 11.4 51408401 + 28.6389 + 28.612 + 13.6 5. How to validate emerging techniques? Different methods generate different absolute values Submitted 2008. Fosser, Duczinski, Agin, Wicker, Darpo

18. QT and arrhythmia issues in drug development. DIA Washington DC, April 2008 Borje Darpo MD PhD 5. How to validate emerging techniques? Apply to data set from more than one TQT study and compare the standard output (time-matched, BL adjusted, placebo-corrected QTcF) with accepted method Result: Good agreement (can be quantitatively defined) Submitted 2008. Fosser, Duczinski, Agin, Wicker, Darpo

19. QT and arrhythmia issues in drug development. DIA Washington DC, April 2008 Borje Darpo MD PhD Another example…. Cross-over, 4 days of moxifloxacin 400 mg qd Not so good agreement

20. QT and arrhythmia issues in drug development. DIA Washington DC, April 2008 Borje Darpo MD PhD

21. QT and arrhythmia issues in drug development. DIA Washington DC, April 2008 Borje Darpo MD PhD

22. QT and arrhythmia issues in drug development. DIA Washington DC, April 2008 Borje Darpo MD PhD Recommendations Validate new measurement methods (techniques) on data set from TQT studies –Ideally, same dataset(s) for all…. Look at data several ways, e.g. –Absolute values in drug-free condition –Time-matched QTcF –Bland Altman plots (slope, LoA) –Proportion of categorical outliers Create quantitative standards for output How to validate new techniques?

23. QT and arrhythmia issues in drug development. DIA Washington DC, April 2008 Borje Darpo MD PhD Conclusions Many of these topics can be studied, thereby allowing unbiased recommendations; The generation of a publicly accessible database comprised of several moxifloxacin / placebo datasets from TQT studies will greatly facilitate this research; Much of this research is ‘precompetitiv’ research – all findings rapidly become public and will not provide anyone individual player competitive edge; Sponsors with experience from many TQT studies can obviously also contribute individually and are encouraged to publish their results.

24. QT and arrhythmia issues in drug development. DIA Washington DC, April 2008 Borje Darpo MD PhD THANK YOU Borje Darpo MD PhD Associate Professor of Cardiology Pharmaceutical Consultant borje.darpo@telia.com