1. Practical Issues to Consider: Design and Analysis of Thorough QT/QTc Study Venkat Sethuraman FDA/Industry Workshop, 14-16 Sept., 2005

2. 2 V Sethuraman/FDA-Industry Workshop/14-16 Sept., 2005 Outline Introduction ICH E14; QT correction methods Study Design Considerations Choice of Baseline; positive control; # of ECG replicates Crossover versus Parallel group Disease specific Considerations Hypotheses & Sample Size Analysis Central Tendency & Categorical Analysis Summary of issues/resolutions

3. 3 V Sethuraman/FDA-Industry Workshop/14-16 Sept., 2005 Background – QT interval QT Correction: QT and RR are correlated so a need for correction. Fridericias correction: QTcF = QT/RR 0.33 Bazetts correction: QTcB =QT/RR 0.5 Pooled correction: QTcP =QT/RR b Individual Correction: QTc i =QT i /RR i bi QTcF & QTci are generally preferred correction for thorough QT study. HR = (60/RR), with RR in sec

4. 4 V Sethuraman/FDA-Industry Workshop/14-16 Sept., 2005 Background - Impact on Type I Error (Simulation) Assume QTcB is the true QT-RR relationship

5. 5 V Sethuraman/FDA-Industry Workshop/14-16 Sept., 2005 Background ICH E14 – Step 4 (25May2005): a negative thorough QT/QTc study is one in which the upper bound of the 95% one-sided confidence interval for the largest time-matched mean effect of the drug on the QTc interval excludes 10 ms. Timing of thorough QT study is usually flexible but required for all new products. This study plays a critical role in determining the intensity of ECG data collection during later stages of drug development. Usually conducted in healthy volunteers but in some instances cannot be conducted due to safety or tolerability concerns (e.g., cytotoxic cancer drugs). ECGs should be manually read. Readers should be blinded to time, treatment and subject (one reader should read all the ECG recordings from a given subject). Cost can be anywhere between $60-100/ECG.

6. 6 V Sethuraman/FDA-Industry Workshop/14-16 Sept., 2005 Study Design Consideration Placebo-controlled study in normal healthy volunteers with a positive control. Parallel versus Crossover Designs Crossover: smaller numbers of subjects; Facilitate QT correction Parallel Group: long half-life drugs; multiple dose Randomization & Blinding Thorough study should it be handled in a same manner as any other pivotal trial. Moxifloxacin visits should not be un-blinded (or single-blind) while keeping all other treatments blinded. This may induce HR differences or cause habituation effects. A crossover study should be period-balanced in all treatments. Do not randomize subjects to receive Moxifloxacin in the first period and in subsequent periods randomized to active treatments. In a parallel group, it is not required to have all subjects receive Moxifloxacin prior to being randomized to active treatments

7. 7 V Sethuraman/FDA-Industry Workshop/14-16 Sept., 2005 Study Design Consideration Crossover Design Example 4-period Williams design with Active (therapeutic & supra-therapeutic dose), placebo and positive control. If active drug is administered under repeat dose conditions (say 5 days of dosing) then, the positive control can be 4 days of placebo + 1 day of moxifloxacin 400 mg. Adequate washout between treatment groups (say at least 1 week) Sample size usually ~50 subjects Parallel Group Subjects randomized to one of 4 treatments Baseline: recommended to have a 0-24 hr profile with time-match for post-dose Sample size usually >~60 / arm Adequate ECG sampling around tmax of active drugs. Appropriate to consider at least 3 replicate ECGs at each time point

8. 8 V Sethuraman/FDA-Industry Workshop/14-16 Sept., 2005 Endpoint: Change from Baseline QTc Baseline definition: Time-matched: Baseline for each session (or treatment) is the avg. of values at a time point (on baseline day) corresponding to the post-dose time point. Pre-dose averaged: Baseline for each session (or treatment) is the average of pre-dose values (~1hr prior to dosing). Time-averaged: Baseline for each session (or treatment) is the average of all values on baseline day.

9. 9 V Sethuraman/FDA-Industry Workshop/14-16 Sept., 2005 Endpoint: Change from Baseline QTc Figure obtained from > Cornel Pater., Methodological considerations in the design of trials for safety assessment of new drugs and chemical entities Current Controlled Trials in Cardiovascular Medicine 2005, 6:1

10. 10 V Sethuraman/FDA-Industry Workshop/14-16 Sept., 2005 Study Design Consideration Choice of Positive Control Moxifloxacin 400 mg (single dose) is usually used as a positive control Any other positive control? quinolones like, gatifloxacin, etc. Effect of Moxifloxacin: The positive control should have an effect on the mean QT/QTc interval of about 5 ms (i.e., an effect that is close to the QT/QTc effect that represents the threshold of regulatory concern, around 5 ms). Detecting the positive controls effect will establish the ability of the study to detect such an effect of the study drug. Absence of a positive control should be justified and alternative methods to establish assay sensitivity provided. Factors that affect the estimation of Moxifloxacin Effect effects similar for Time-matched, time averaged or pre-dose averaged baseline ? the upper bound of the 95% one-sided confidence interval for the largest time- matched mean effect of the moxi relative to placebo OR Max. mean QTc effect of Moxi (unadjusted for placebo)? Effects using QTci tends to be smaller than QTcF or QTcB.

11. 11 V Sethuraman/FDA-Industry Workshop/14-16 Sept., 2005 Impact of Positive Control –Positive control shows >5ms effect (say QTcF) and active treatment shows or does not show effect –Outcome: the study results are valid. –If effect of Moxi>12-15ms, are the study results still valid? –depends on subject population, correction method, baseline, days of separation from baseline to post-dose, etc. –Positive control shows <5 ms effect –If active treatment shows no effect, then it is a failed study or need to show alternate means of establishing assay sensitivity. If active treatment shows a positive effect (say >15ms), does the effect of study drug still valid?

12. 12 V Sethuraman/FDA-Industry Workshop/14-16 Sept., 2005 Treatment Estimates from Crossover Baseline Method Trt (QTci)Point Estimate* 90% CI Time-avg.Placebo-5(-7, -2.7) Moxi3.5(1.3, 5.7) Moxi-Placebo8.5(7.6, 9.3) Time-matchPlacebo-5.8(-8.9, -2.8) Moxi6.8(3.8, 9.8) Moxi-Placebo (occurred at 1hr) 12.6(9.7, 15.6) Pre-dose avg.Placebo-3.8(-5.6, -2.1) Moxi5.0(3.3, 6.8) Moxi-Placebo8.8(8.0, 9.7) * Arth. Mean or LS mean difference

13. 13 V Sethuraman/FDA-Industry Workshop/14-16 Sept., 2005 Categorical Results Time-matchedTime-averaged /pre-dose avg. CategoryPlaceboMoxiPlaceboMoxi CFB QTc >30 ms<1%3.5%0% *Subjects were included if they had both baseline and post-dose measurements; ECG values at a time point was an average of 3 replicate measurement. Increase in QTc> 30, 60 msec Categorical results might be affected if a diurnal variation in QTc is ignored.

14. 14 V Sethuraman/FDA-Industry Workshop/14-16 Sept., 2005 Moxifloxacin Treatment Estimates Published ParameterComparisonPoint Estimate90% or 95% CI QTcF 1 * Moxifloxacin 400 mg13.9 (SD=15) QTcF 2 * Moxi 400mg – Placebo12.7(8.6, 16.8) QTci 2 * Moxi 400mg – Placebo11.1(7.2, 15) QTcF 3 ^ Moxi 400mg – Placebo8(6, 9) QTci 3 ^ Moxi 400mg – Placebo7(5, 8) QTcF 4 + Moxi 400mg – Placebo11, 12, 16 (7, 14) (8, 17) (12, 21) 1: Moxifloxacin SBA: Mean (SD) change from baseline QTc at Cmax using corresponding time on Placebo Day as baseline 2. Alfuzosin QT study, and 3. Vardenafil QT study http://www.fda.gov/ohrms/dockets/ac/03/briefing/3956B1_01_FDA-alfuzosin.htm http://www.fda.gov/ohrms/dockets/ac/03/briefing/3956B1_01_FDA-alfuzosin.htm 4. Vesicare QT study: http://www.vesicare.com/pdf/vesicare_prescribing_info.pdfhttp://www.vesicare.com/pdf/vesicare_prescribing_info.pdf

15. 15 V Sethuraman/FDA-Industry Workshop/14-16 Sept., 2005 Baseline Differences in a Crossover (An Example)

16. 16 V Sethuraman/FDA-Industry Workshop/14-16 Sept., 2005 Impact of Baseline on QT correction Pre-dose data used for QT correction 3 pre-dose per period x 3-period Estimates of QT correction may be unreliable Difference can be as high as 40-50 ms for some subjects Pre-dose + placebo treatment (crossover only) All pre-dose + 12 post-dose time points (placebo) Assume that placebo occurs equal number of times/period Estimates could be different for placebo on period 3 (?) Baseline day profile (0-24 hr) All 12 baseline time points (each 3 ECG/time point)

17. Time-matchPre-dosePre-dose + placebo

18. 18 V Sethuraman/FDA-Industry Workshop/14-16 Sept., 2005 Impact on QT Correction Method

19. 19 V Sethuraman/FDA-Industry Workshop/14-16 Sept., 2005 Impact on QT Correction Method

20. 20 V Sethuraman/FDA-Industry Workshop/14-16 Sept., 2005 Endpoint and Hypotheses From E14:... The upper bound of the 95% one-sided confidence interval for the largest time-matched mean effect of the drug on the QTc interval excludes 10 ms. To construct a CI for largest time-matched difference is a difficult statistical problem Impact on type II error (sponsor s risk) while planning these trials Intersection-Union Hypothesis -Mean CFB QTc for study drug and placebo & -k refers to # of time points

21. 21 V Sethuraman/FDA-Industry Workshop/14-16 Sept., 2005 Hypotheses Hochberg and Thamane (1987) - Multiple time points does not have any impact on the type I error rate (public risk). I-U Test does not assure overall power of the test (sponsors risk), i.e., the more time points you test, the higher the chance of type II error. Since observations within same subject (time points) are possibly correlated, it is expected that K hypotheses are also correlated. Not aware of statistical methodology to obtain sample size accounting for the correlation. Result from Simulation accounting for correlation.

22. 22 V Sethuraman/FDA-Industry Workshop/14-16 Sept., 2005 Hypotheses and Sample Size Need to an understand the correlation structure and a prior estimate of. Assume AR(1) =0.1 True treatment difference (active- placebo) = 2 ms. Number of time points = 5 Sample size increases from n=62 per arm to 80 per arm to maintain power at 90%. Sample size decreases to n=70 if correlation is assumed to be =0.5 Impact on sample size minimal if k>5. From Simulation

23. 23 V Sethuraman/FDA-Industry Workshop/14-16 Sept., 2005 Disease Specific Consideration (e.g., cytotoxic cancer drugs). It may not be feasible to include positive control or even placebo Limited baseline values May not be possible to study in healthy volunteers Uncertain in terms of positive control effects May not be possible to achieve supra-therapeutic dose Use PK-QT modeling to predict at higher dose Use Monte Carlo simulation to simulate models with fixed and random effects to determine the expected value of the model.

24. 24 V Sethuraman/FDA-Industry Workshop/14-16 Sept., 2005 Disease Specific Consideration An example using PK-QT simulation Consider a thorough QT study conducted at therapeutic dose in healthy volunteers Due to toxicity of drug, a supra- therapeutic dose is not possible in healthy but PK exposure available from DDI study in patients. Develop PK-QT models & use simulation to predict QT effects at higher exposure.

25. 25 V Sethuraman/FDA-Industry Workshop/14-16 Sept., 2005 Conclusion Though QT study should be treated as any pivotal trial and should use robust design features. In general, Crossover designs are preferred. Proper attention should be given to the choice of positive control and expected effect size. Baseline should be adequate to address both the central tendency analysis and categorical analysis. Sample size should be adequately powered to protect type II error in the I-U hypothesis testing. PK-QT modeling is highly recommended for all thorough QT study.

26. 26 V Sethuraman/FDA-Industry Workshop/14-16 Sept., 2005 Reference Bazett JC. An anlysis of time relations of electocardigrams. Heart 1920; 7:353- 367. Fridericia LS. Die Systolendauer im Elektrokardiogramm bei normalen Menschen und bei Herzkranken. Acta Medica Scandinavia 1920; 53:469-486 Malik M. Problems of heart rate correction in the assessment of drug-induced QT interval prolongation. Journal of Cardiovascular Electrophysiology 2003; 12:411- 420 Evaluation of Vardenafil and Sildenafil on Cardiac Repolarization, Morganroth J, Ilson BE, Shaddinger BC, Dabiri GA, Patel BR, Boyle DA, Sethuraman VS, Montague TH, - The American Journal of Cardiology, 2004 5.Leslie Kenna, et. al., Clinical Pharmacology Subcommittee of the Advisory Committee for Pharmaceutical Science (2003) 6.ICH E14: The Clinical Evaluation Of Qt/Qtc Interval Prolongation And Proarrhythmic Potential For Non-antiarrhythmic Drugs (http://www.emea.eu.int/pdfs/human/ich/000204en.pdf)http://www.emea.eu.int/pdfs/human/ich/000204en.pdf 7.Patterson S., et al. (2003). Investigating drug-induced QT and QTc prolongation in the clinic: statistical design and analysis considerations. Report from the Pharmaceutical Research and Manufacturers of America QT Statistics Expert Working Team

27. 27 V Sethuraman/FDA-Industry Workshop/14-16 Sept., 2005 Acknowledgements Timothy Montague, GSK Tianyu Li, Fox Chase Cancer Center, PA. GSK QT Steering committee Novartis QT sub-group Joel Morganroth, eRT, PA Lixia Wang, Novartis, NJ Organizers: Sue Walker, George Rochester and Tim Montague