QTc Trials

Presented By:

Ad Roffel, Ph.D.PRA International EDS NLP.O. Box 200, 9470 AE Zuidlaren, The NetherlandsTel: +31 50 402 22 22Fax: +31 50 402 22 23

-Adopted guidance-Clinical execution-Outcome-Conclusions

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QT/QTc-interval

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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HC Draft Guidance• March 2001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)

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Adopted Guidance - Contents

All new drugs require thorough QTc trial, irrespective of preclinical profileAlso 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

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Adopted GuidanceClinical Execution• Planning• Design• Safety• Operational• Data analysis

OutcomeConclusions

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Place in development programAs early as possibleAfter 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

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Timing, timelinesTime 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

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Adopted GuidanceClinical Execution• Planning• Design• Safety• Operational• Data analysis

OutcomeConclusions

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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

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Design - Positive control

Assay sensitivity vs. reference for outcomeMoxifloxacin• 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 characterizedPositive control can be open, no need to blind

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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

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Design - Variability in QTc

30%

40%

50%

60%

70%

80%

90%

100%

0 10 20 30 40 50 60 70

number of subjects (n)

Po

wer

(%)

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Design - Sources of QTc variability

Correction for heart rate (RR): individual correction method (QTci)• Alternatives: Bazett, Fredericia (QTcB, QTcF) – required for historic

reasonsDiurnal variation • Usually 12-16 time-points over 24 h with at least 3 ECGs at each time

point• ECGs should cover Cmax 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 dayECG collection and QT measurement (validated core ECG laboratory)• Digital processing, manual evaluation

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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

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Design - Options

Therapeutic doseSupra-therapeutic dosePositive controlPlacebo

Cross-over

Parallel

Alternative parallel

N=50

N=200

N=150

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