1. QTc Trials Presented By: Ad Roffel, Ph.D. PRA International EDS NL P.O. Box 200, 9470 AE Zuidlaren, The Netherlands Tel: +31 50 402 22 22 Fax: +31 50 402 22 23 -Adopted guidance -Clinical execution -Outcome -Conclusions

2. The Project Assurance ® Difference 2 QT/QTc-interval

3. The Project Assurance ® Difference 3 Adopted Guidance Clinical Execution Outcome Conclusions

4. The Project Assurance ® Difference 4 Adopted Guidance - History CPMP Points to Consider December 1997 HC Draft Guidance March 2001 FDA/HC Concept Paper November 2002 Adopted as ICH Topic July 2003 (Step 1) ICH Final Draft Text May 2005 (Step 4) Current Practice October 2005 (FDA) November 2005 (CHMP)

5. The Project Assurance ® Difference 5 Adopted Guidance - Contents All new drugs require thorough QTc trial, irrespective of preclinical profile Also required for approved products that apply for new registration (dose, indication, target population, route of administration) Needs to define a 5-ms effect with a one-sided 95% CI that excludes a 10-ms effect, using time-matched methods with 3-5 ECGs per time point Randomised, double-blind, placebo, positive control, therapeutic dose level, supratherapeutic dose level (multiples of the maximum expected concentration), healthy volunteers New, complex, expensive study required for all registration dossiers

6. The Project Assurance ® Difference 6 Adopted Guidance Clinical Execution Planning Design Safety Operational Data analysis Outcome Conclusions

7. The Project Assurance ® Difference 7 Place in development program As early as possible After PK and metabolism have been sufficiently characterized Cmax of parent and active metabolites Dose regimen in therapeutic use Supratherapeutic dose Outcome may direct intensity of ECG monitoring in Phase III Early to late Phase II Clinical Execution - Planning

8. The Project Assurance ® Difference 8 Timing, timelines Time from RFP to First-Subject-In: 3 - 4 months thorough discussion on design (Sponsor, CRO, FDA) big studies: proper preparation, timely recruitment First-Subject-In to Last-Subject-Out: 4 weeks - 3 months single dose, 4-way cross-over (n=44 subjects) parallel, multiple dose titration (n=80 subjects) Clinical Execution - Planning

9. The Project Assurance ® Difference 9 Adopted Guidance Clinical Execution Planning Design Safety Operational Data analysis Outcome Conclusions

10. The Project Assurance ® Difference 10 Design – Supratherapeutic dose (E14) Worst case exposure should be mimicked (“substantial multiples of anticipated maximum therapeutic exposure”) genetic variation, concomitant disease or medication Use of metabolic inhibitors to reach supratherapeutic plasma concentrations may be considered Experience (FDA) Supratherapeutic dose 2- to 20-fold therapeutic dose (median: 4-fold) (PBR) 2- to 10-fold (5-fold); Maximum Tolerated Dose, or maximum dose ever given

11. The Project Assurance ® Difference 11 Design - Positive control Assay sensitivity vs. reference for outcome Moxifloxacin Widely used Consistent QTc-prolongation of 6-15 ms at 400 mg p.o. No risk of TdP Single dose is sufficient, also in multiple dose designs Drug from same class could serve as reference, but usually less characterized Positive control can be open, no need to blind

12. The Project Assurance ® Difference 12 Design - Sample size Postulated drug-induced effect (e.g., 0 ms, 3 ms, 6 ms) Intra- / inter-subject variability (SD) in QTc (6-12 ms) Upper bound 95% CI to be excluded (10 ms) Required power

13. The Project Assurance ® Difference 13 Design - Variability in QTc

14. The Project Assurance ® Difference 14 Design - Sources of QTc variability Correction for heart rate (RR): individual correction method (QTci) Alternatives: Bazett, Fredericia (QTcB, QTcF) – required for historic reasons Diurnal variation Usually 12-16 time-points over 24 h with at least 3 ECGs at each time point ECGs should cover C max of parent and metabolites Population: male and female healthy volunteers, age 18-45 (65) Conditions of the ECG collection Supine rest, mental activity, before blood sampling, meals Proper design of baseline day ECG collection and QT measurement (validated core ECG laboratory) Digital processing, manual evaluation

15. The Project Assurance ® Difference 15 Design – Inclusion criteria Age Classically: 18-45 years (higher age increases frequency of co ‑ morbidity) In specific cases: relate to target population Gender Males and females required: at least 40% each Race Limited data: unclear whether ethnic factors play a role in QTc prolongation Smoking habits Classically: non- or light smokers allowed

16. The Project Assurance ® Difference 16 Design - Options Therapeutic dose Supra-therapeutic dose Positive control Placebo Cross-over Parallel Alternative parallel N=50 N=200 N=150

17. The Project Assurance ® Difference 17 Click here to continue